chr16-89739506-T-C

Variant names:

• chr16-89739506-T-C
• rs9282681
• NM_000135.4:c.3982A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.3982A>G​(p.Thr1328Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0777 in 1,551,258 control chromosomes in the GnomAD database, including 5,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1328I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.060 (421 hom., cov: 33)
  • Exomes 𝑓: 0.080 (5141 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:9 O:1
• Conservation: PhyloP100: -0.994
• Publications: 31 publications found

Genes affected

FANCA (HGNC:3582): (FA complementation group A) The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1 (also called BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ (also called BRIP1), FANCL, FANCM and FANCN (also called PALB2). The previously defined group FANCH is the same as FANCA. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA crosslinking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation group A. Alternative splicing results in multiple transcript variants encoding different isoforms. Mutations in this gene are the most common cause of Fanconi anemia. [provided by RefSeq, Jul 2008]

ZNF276 (HGNC:23330): (zinc finger protein 276) Enables sequence-specific double-stranded DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Located in kinetochore. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 25 uncertain in NM_000135.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.007843435).
• BP6: Variant 16-89739506-T-C is Benign according to our data. Variant chr16-89739506-T-C is described in ClinVar as Benign. ClinVar VariationId is 134278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.209 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000135.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	NM_000135.4	MANE Select	c.3982A>G	p.Thr1328Ala	missense	Exon 40 of 43	NP_000126.2
	ZNF276	NM_001113525.2	MANE Select	c.*1260T>C		3_prime_UTR	Exon 11 of 11	NP_001106997.1
	FANCA	NM_001286167.3		c.3982A>G	p.Thr1328Ala	missense	Exon 40 of 43	NP_001273096.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.3982A>G	p.Thr1328Ala	missense	Exon 40 of 43	ENSP00000373952.3
	ZNF276	ENST00000443381.7	TSL:1 MANE Select	c.*1260T>C		3_prime_UTR	Exon 11 of 11	ENSP00000415836.2
	ZNF276	ENST00000289816.9	TSL:1	c.*1260T>C		3_prime_UTR	Exon 11 of 11	ENSP00000289816.5

Frequencies

GnomAD3 genomes AF: 0.0596 AC: 9071 AN: 152126 Hom.: 420 Cov.: 33

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0376

Gnomad ASJ AF: 0.0580

Gnomad EAS AF: 0.218

Gnomad SAS AF: 0.0263

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0833

Gnomad OTH AF: 0.0569

GnomAD2 exomes AF: 0.0661 AC: 10322 AN: 156058 AF XY: 0.0661

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0563

Gnomad EAS exome AF: 0.238

Gnomad FIN exome AF: 0.0609

Gnomad NFE exome AF: 0.0803

Gnomad OTH exome AF: 0.0568

GnomAD4 exome AF: 0.0797 AC: 111444 AN: 1399014 Hom.: 5141 Cov.: 34 AF XY: 0.0783 AC XY: 54032 AN XY: 690082

African (AFR) AF: 0.0112 AC: 353 AN: 31602

American (AMR) AF: 0.0226 AC: 807 AN: 35716

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 1419 AN: 25184

East Asian (EAS) AF: 0.153 AC: 5481 AN: 35758

South Asian (SAS) AF: 0.0222 AC: 1758 AN: 79256

European-Finnish (FIN) AF: 0.0579 AC: 2835 AN: 48966

Middle Eastern (MID) AF: 0.0134 AC: 73 AN: 5432

European-Non Finnish (NFE) AF: 0.0870 AC: 93899 AN: 1079098

Other (OTH) AF: 0.0831 AC: 4819 AN: 58002

GnomAD4 genome AF: 0.0596 AC: 9078 AN: 152244 Hom.: 421 Cov.: 33 AF XY: 0.0575 AC XY: 4280 AN XY: 74430

African (AFR) AF: 0.0139 AC: 579 AN: 41540

American (AMR) AF: 0.0375 AC: 574 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0580 AC: 201 AN: 3466

East Asian (EAS) AF: 0.219 AC: 1135 AN: 5178

South Asian (SAS) AF: 0.0272 AC: 131 AN: 4822

European-Finnish (FIN) AF: 0.0613 AC: 651 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0833 AC: 5664 AN: 68004

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0782 Hom.: 1148

Bravo AF: 0.0572

TwinsUK AF: 0.0984 AC: 365

ALSPAC AF: 0.0823 AC: 317

ESP6500AA AF: 0.0136 AC: 57

ESP6500EA AF: 0.0706 AC: 579

ExAC AF: 0.0307 AC: 2659

Asia WGS AF: 0.113 AC: 392 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Pathogenic:1 Benign:4

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Aug 23, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 28, 2020

Leiden Open Variation Database

Significance: Pathogenic

Review Status: flagged submission

Collection Method: curation

Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.

Jul 10, 2025

GeneKor MSA

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2 Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 18, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: FANCA c.3982A>G (p.Thr1328Ala) results in a non-conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.066 in 156058 control chromosomes in the gnomAD database, including 617 homozygotes. The observed variant frequency is approximately 30.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is benign. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five classified the variant as benign while one classified as pathogenic. Based on the evidence outlined above, the variant was classified as benign.

not provided Benign:2

Mar 12, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31586946, 9371798, 27121516)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Fanconi anemia Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.11
DANN	Benign	0.44
DEOGEN2	Benign	0.14	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.83	L
PhyloP100		-0.99
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.20
Sift	Benign	0.44	T
Sift4G	Benign	0.26	T
Polyphen		0.0050	B
Vest4		0.017
ClinPred		0.00030	T
GERP RS		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.10
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9282681; hg19: chr16-89805914; COSMIC: COSV57066209; COSMIC: COSV57066209;