rs1800338

chr16-89775812-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_000135.4(FANCA):c.1830A>G(p.Ala610=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00237 in 1,609,898 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: FANCA NM_000135.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.215

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-89775812-T-C is Benign according to our data. Variant chr16-89775812-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 237037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-89775812-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.215 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00196 (299/152302) while in subpopulation NFE AF= 0.00335 (228/68026). AF 95% confidence interval is 0.00299. There are 1 homozygotes in gnomad4. There are 136 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1830A>G	p.Ala610=	synonymous_variant	21/43	ENST00000389301.8
FANCA	NM_001286167.3	c.1830A>G	p.Ala610=	synonymous_variant	21/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1830A>G	p.Ala610=	synonymous_variant	21/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 299 AN: 152184 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00335

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00174 AC: 430 AN: 247414 Hom.: 0 AF XY: 0.00183 AC XY: 245 AN XY: 133722

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.000586

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000669

Gnomad FIN exome AF: 0.00131

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.000825

GnomAD4 exome AF: 0.00241 AC: 3511 AN: 1457596 Hom.: 5 Cov.: 29 AF XY: 0.00232 AC XY: 1683 AN XY: 724964

Gnomad4 AFR exome AF: 0.000599

Gnomad4 AMR exome AF: 0.000653

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000549

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00289

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00196 AC: 299 AN: 152302 Hom.: 1 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74476

Gnomad4 AFR AF: 0.000602

Gnomad4 AMR AF: 0.00177

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.000942

Gnomad4 NFE AF: 0.00335

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00228 Hom.: 1

Bravo AF: 0.00182

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 25, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia Benign:3

Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 30, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	FANCA: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 10, 2021	This variant is associated with the following publications: (PMID: 23021409) -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Fanconi anemia complementation group A Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 09, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
Cadd	Benign	4.7
Dann	Benign	0.64
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1800338; hg19: chr16-89842220; COSMIC: COSV104699320;