16-89740825-C-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000135.4(FANCA):c.3807G>C(p.Leu1269Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0955 in 1,612,704 control chromosomes in the GnomAD database, including 8,122 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 977 hom., cov: 31)

Exomes 𝑓: 0.094 ( 7145 hom. )

Consequence

FANCA
NM_000135.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.0120

Variant links:

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 links:

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]

ZNF276 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 16-89740825-C-G is Benign according to our data. Variant chr16-89740825-C-G is described in ClinVar as [Benign]. Clinvar id is 255263.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.012 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.213 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FANCA	NM_000135.4 link	c.3807G>C	p.Leu1269Leu	synonymous_variant	Exon 38 of 43	ENST00000389301.8	NP_000126.2	O15360-1
ZNF276	NM_001113525.2 link	c.*2579C>G		3_prime_UTR_variant	Exon 11 of 11	ENST00000443381.7	NP_001106997.1	Q8N554-1I6L9I3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FANCA	ENST00000389301.8 link	c.3807G>C	p.Leu1269Leu	synonymous_variant	Exon 38 of 43	1	NM_000135.4	ENSP00000373952.3		O15360-1
ZNF276	ENST00000443381.7 link	c.*2579C>G		3_prime_UTR_variant	Exon 11 of 11	1	NM_001113525.2	ENSP00000415836.2		Q8N554-1

Frequencies

GnomAD3 genomes

AF:

0.105

AC:

15925

AN:

151874

Hom.:

974

Cov.:

show subpopulations

Gnomad AFR

AF:

0.140

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.0551

Gnomad ASJ

AF:

0.0793

Gnomad EAS

AF:

0.223

Gnomad SAS

AF:

0.118

Gnomad FIN

AF:

0.0719

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0930

Gnomad OTH

AF:

0.0952

GnomAD3 exomes

AF:

0.0931

AC:

23291

AN:

250288

Hom.:

1440

AF XY:

0.0930

AC XY:

12583

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.144

Gnomad AMR exome

AF:

0.0300

Gnomad ASJ exome

AF:

0.0770

Gnomad EAS exome

AF:

0.232

Gnomad SAS exome

AF:

0.104

Gnomad FIN exome

AF:

0.0721

Gnomad NFE exome

AF:

0.0861

Gnomad OTH exome

AF:

0.0763

GnomAD4 exome

AF:

0.0945

AC:

138003

AN:

1460712

Hom.:

7145

Cov.:

AF XY:

0.0947

AC XY:

68803

AN XY:

726602

show subpopulations

Gnomad4 AFR exome

AF:

0.143

Gnomad4 AMR exome

AF:

0.0331

Gnomad4 ASJ exome

AF:

0.0755

Gnomad4 EAS exome

AF:

0.165

Gnomad4 SAS exome

AF:

0.103

Gnomad4 FIN exome

AF:

0.0705

Gnomad4 NFE exome

AF:

0.0936

Gnomad4 OTH exome

AF:

0.104

GnomAD4 genome

AF:

0.105

AC:

15943

AN:

151992

Hom.:

977

Cov.:

AF XY:

0.102

AC XY:

7598

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.140

Gnomad4 AMR

AF:

0.0549

Gnomad4 ASJ

AF:

0.0793

Gnomad4 EAS

AF:

0.224

Gnomad4 SAS

AF:

0.119

Gnomad4 FIN

AF:

0.0719

Gnomad4 NFE

AF:

0.0929

Gnomad4 OTH

AF:

0.0952

Alfa

AF:

0.0660

Hom.:

144

Bravo

AF:

0.105

Asia WGS

AF:

0.166

AC:

577

AN:

3478

EpiCase

AF:

0.0884

EpiControl

AF:

0.0845

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fanconi anemia complementation group A

Benign:4

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 08, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided

Benign:2

Feb 02, 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

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.53

DANN

Benign

0.63

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over