rs183513839

chr16-89778789-G-Achr16-89778789-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000135.4(FANCA):c.1826+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00657 in 1,613,028 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (41 hom.)
• Consequence: FANCA NM_000135.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.44

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 16-89778789-G-A is Benign according to our data. Variant chr16-89778789-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 210972.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89778789-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00513 (780/152144) while in subpopulation AMR AF= 0.00872 (133/15252). AF 95% confidence interval is 0.00751. There are 2 homozygotes in gnomad4. There are 399 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1826+12C>T		intron_variant		ENST00000389301.8
FANCA	NM_001286167.3	c.1826+12C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1826+12C>T		intron_variant		1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 781 AN: 152028 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00873

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00928

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00666

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00603 AC: 1516 AN: 251484 Hom.: 5 AF XY: 0.00641 AC XY: 871 AN XY: 135918

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.00347

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.00942

Gnomad NFE exome AF: 0.00835

Gnomad OTH exome AF: 0.00668

GnomAD4 exome AF: 0.00672 AC: 9816 AN: 1460884 Hom.: 41 Cov.: 34 AF XY: 0.00663 AC XY: 4820 AN XY: 726836

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00396

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00553

Gnomad4 FIN exome AF: 0.0100

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00578

GnomAD4 genome AF: 0.00513 AC: 780 AN: 152144 Hom.: 2 Cov.: 32 AF XY: 0.00536 AC XY: 399 AN XY: 74374

Gnomad4 AFR AF: 0.00140

Gnomad4 AMR AF: 0.00872

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00928

Gnomad4 NFE AF: 0.00666

Gnomad4 OTH AF: 0.00664

Alfa AF: 0.00544 Hom.: 0

Bravo AF: 0.00518

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 27, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 13, 2021	- -

Fanconi anemia complementation group A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

FANCA: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
Cadd	Benign	0.18
Dann	Benign	0.40

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: rs183513839; hg19: chr16-89845197; COSMIC: COSV104699314;