NM_000135.4:c.4332T>G

Variant names:

• chr16-89738637-A-C
• rs149531696
• NM_000135.4:c.4332T>G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000135.4(FANCA):​c.4332T>G​(p.Pro1444Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000728 in 1,613,620 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00075 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00073 (5 hom.)
• Consequence: FANCA NM_000135.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.06

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 16-89738637-A-C is Benign according to our data. Variant chr16-89738637-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 255268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89738637-A-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.06 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000725 (1060/1461312) while in subpopulation MID AF= 0.00413 (23/5574). AF 95% confidence interval is 0.00282. There are 5 homozygotes in gnomad4_exome. There are 555 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4	c.4332T>G	p.Pro1444Pro	synonymous_variant	Exon 43 of 43	ENST00000389301.8	NP_000126.2
ZNF276	NM_001113525.2	c.*391A>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000443381.7	NP_001106997.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8	c.4332T>G	p.Pro1444Pro	synonymous_variant	Exon 43 of 43	1	NM_000135.4	ENSP00000373952.3
ZNF276	ENST00000443381.7	c.*391A>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_001113525.2	ENSP00000415836.2

Frequencies

GnomAD3 genomes AF: 0.000749 AC: 114 AN: 152190 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000691

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00112 AC: 277 AN: 248102 Hom.: 2 AF XY: 0.00122 AC XY: 164 AN XY: 134518

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.000579

Gnomad ASJ exome AF: 0.0110

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00101

Gnomad OTH exome AF: 0.00213

GnomAD4 exome AF: 0.000725 AC: 1060 AN: 1461312 Hom.: 5 Cov.: 31 AF XY: 0.000763 AC XY: 555 AN XY: 726936

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.0108

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000731

Gnomad4 FIN exome AF: 0.0000941

Gnomad4 NFE exome AF: 0.000496

Gnomad4 OTH exome AF: 0.00172

GnomAD4 genome AF: 0.000748 AC: 114 AN: 152308 Hom.: 0 Cov.: 33 AF XY: 0.000833 AC XY: 62 AN XY: 74474

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.0141

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000691

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00145 Hom.: 1

Bravo AF: 0.000740

EpiCase AF: 0.00125

EpiControl AF: 0.00166

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

FANCA: BP4, BP7 -

Apr 01, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

Apr 23, 2020

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Oct 04, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Fanconi anemia Benign:1

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fanconi anemia complementation group A Benign:1

May 30, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.057
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs149531696; hg19: chr16-89805045;