rs17232910

chr16-89773358-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000135.4(FANCA):c.1927C>G(p.Pro643Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.078 in 1,550,812 control chromosomes in the GnomAD database, including 5,683 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P643R) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.060 (437 hom., cov: 32)
  • Exomes 𝑓: 0.080 (5246 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 0.0740

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 (MetaRNN=0.0039646924).
• BP6: Variant 16-89773358-G-C is Benign according to our data. Variant chr16-89773358-G-C is described in ClinVar as [Benign]. Clinvar id is 134247.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.1927C>G	p.Pro643Ala	missense_variant	22/43	ENST00000389301.8
FANCA	NM_001286167.3	c.1927C>G	p.Pro643Ala	missense_variant	22/43

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.1927C>G	p.Pro643Ala	missense_variant	22/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 9162 AN: 152146 Hom.: 436 Cov.: 32

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.0230

Gnomad AMR AF: 0.0379

Gnomad ASJ AF: 0.0591

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.0269

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0834

Gnomad OTH AF: 0.0550

GnomAD3 exomes AF: 0.0677 AC: 10573 AN: 156116 Hom.: 676 AF XY: 0.0674 AC XY: 5538 AN XY: 82116

Gnomad AFR exome AF: 0.0142

Gnomad AMR exome AF: 0.0211

Gnomad ASJ exome AF: 0.0571

Gnomad EAS exome AF: 0.257

Gnomad SAS exome AF: 0.0217

Gnomad FIN exome AF: 0.0594

Gnomad NFE exome AF: 0.0809

Gnomad OTH exome AF: 0.0585

GnomAD4 exome AF: 0.0800 AC: 111828 AN: 1398546 Hom.: 5246 Cov.: 31 AF XY: 0.0786 AC XY: 54209 AN XY: 689814

Gnomad4 AFR exome AF: 0.0111

Gnomad4 AMR exome AF: 0.0227

Gnomad4 ASJ exome AF: 0.0578

Gnomad4 EAS exome AF: 0.163

Gnomad4 SAS exome AF: 0.0225

Gnomad4 FIN exome AF: 0.0569

Gnomad4 NFE exome AF: 0.0870

Gnomad4 OTH exome AF: 0.0839

GnomAD4 genome AF: 0.0602 AC: 9169 AN: 152266 Hom.: 437 Cov.: 32 AF XY: 0.0582 AC XY: 4337 AN XY: 74460

Gnomad4 AFR AF: 0.0140

Gnomad4 AMR AF: 0.0378

Gnomad4 ASJ AF: 0.0591

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.0278

Gnomad4 FIN AF: 0.0613

Gnomad4 NFE AF: 0.0834

Gnomad4 OTH AF: 0.0553

Alfa AF: 0.0805 Hom.: 433

Bravo AF: 0.0580

TwinsUK AF: 0.0987 AC: 366

ALSPAC AF: 0.0830 AC: 320

ESP6500AA AF: 0.0125 AC: 51

ESP6500EA AF: 0.0659 AC: 519

ExAC AF: 0.0245 AC: 1457

Asia WGS AF: 0.117 AC: 407 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fanconi anemia complementation group A Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 06, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	0.76
Dann	Benign	0.37
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.5	N;N
REVEL	Benign	0.23
Sift	Benign	0.45	T;T
Sift4G	Benign	0.39	T;T
Polyphen		0.0010	B;.
Vest4		0.032
ClinPred		0.0011	T
GERP RS		-2.4
RBP_binding_hub_radar		1.0
RBP_regulation_power_radar		2.1
Varity_R		0.019
gMVP		0.24

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: rs17232910; hg19: chr16-89839766; COSMIC: COSV66879987; COSMIC: COSV66879987;