chr16-89816592-G-C

Variant names:

• chr16-89816592-G-C
• rs76275444
• NM_000135.4:c.24C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):​c.24C>G​(p.Asn8Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00826 in 1,527,118 control chromosomes in the GnomAD database, including 980 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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 Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N8S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (548 hom., cov: 34)
  • Exomes 𝑓: 0.0042 (432 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:9 O:1
• Conservation: PhyloP100: -2.25
• Publications: 5 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]

FANCA Gene-Disease associations (from GenCC):

• Fanconi anemia complementation group A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P
• Fanconi anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013244152).
• BP6: Variant 16-89816592-G-C is Benign according to our data. Variant chr16-89816592-G-C is described in ClinVar as Benign. ClinVar VariationId is 134236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 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.24C>G	p.Asn8Lys	missense	Exon 1 of 43	NP_000126.2
	FANCA	NM_001286167.3		c.24C>G	p.Asn8Lys	missense	Exon 1 of 43	NP_001273096.1
	FANCA	NM_001018112.3		c.24C>G	p.Asn8Lys	missense	Exon 1 of 11	NP_001018122.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FANCA	ENST00000389301.8	TSL:1 MANE Select	c.24C>G	p.Asn8Lys	missense	Exon 1 of 43	ENSP00000373952.3
	FANCA	ENST00000563673.5	TSL:1	c.24C>G	p.Asn8Lys	missense	Exon 1 of 10	ENSP00000456443.1
	FANCA	ENST00000534992.5	TSL:1	c.24C>G	p.Asn8Lys	missense	Exon 1 of 11	ENSP00000443675.1

Frequencies

GnomAD3 genomes AF: 0.0449 AC: 6828 AN: 152086 Hom.: 546 Cov.: 34

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000574

Gnomad OTH AF: 0.0268

GnomAD2 exomes AF: 0.00495 AC: 614 AN: 124034 AF XY: 0.00395

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.00771

Gnomad ASJ exome AF: 0.000130

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000162

Gnomad OTH exome AF: 0.00380

GnomAD4 exome AF: 0.00420 AC: 5778 AN: 1374924 Hom.: 432 Cov.: 31 AF XY: 0.00360 AC XY: 2444 AN XY: 679488

African (AFR) AF: 0.159 AC: 4644 AN: 29140

American (AMR) AF: 0.00868 AC: 310 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.0000404 AC: 1 AN: 24732

East Asian (EAS) AF: 0.00 AC: 0 AN: 34276

South Asian (SAS) AF: 0.000320 AC: 25 AN: 78220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33714

Middle Eastern (MID) AF: 0.00472 AC: 21 AN: 4446

European-Non Finnish (NFE) AF: 0.000190 AC: 205 AN: 1077366

Other (OTH) AF: 0.00998 AC: 572 AN: 57332

GnomAD4 genome AF: 0.0449 AC: 6832 AN: 152194 Hom.: 548 Cov.: 34 AF XY: 0.0432 AC XY: 3217 AN XY: 74426

African (AFR) AF: 0.156 AC: 6499 AN: 41536

American (AMR) AF: 0.0154 AC: 235 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000574 AC: 39 AN: 67982

Other (OTH) AF: 0.0265 AC: 56 AN: 2110

Alfa AF: 0.00167 Hom.: 3

Bravo AF: 0.0509

ESP6500AA AF: 0.100 AC: 326

ESP6500EA AF: 0.000285 AC: 2

ExAC AF: 0.00522 AC: 510

Asia WGS AF: 0.00609 AC: 22 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Uncertain:1 Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jun 12, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

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: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: curation

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

not specified Benign:2 Other:1

Mar 30, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Benign:2

Mar 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Fanconi anemia Benign:1

Feb 03, 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	0.13
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	0.033
DANN	Benign	0.60
DEOGEN2	Benign	0.072	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.53	T
MetaRNN	Benign	0.0013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-2.2
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.055
Sift	Benign	0.23	T
Sift4G	Benign	0.60	T
Polyphen		0.0080	B
Vest4		0.13
MutPred		0.15		Gain of ubiquitination at N8 (P = 0.0069)
MVP		0.59
ClinPred		0.011	T
GERP RS		-8.4
PromoterAI		0.043	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.051
gMVP		0.064
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs76275444; hg19: chr16-89883000;