rs144917960

chr16-89805388-G-Achr16-89805388-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000135.4(FANCA):c.601C>T(p.Pro201Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00269 in 1,612,398 control chromosomes in the GnomAD database, including 122 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P201P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (16 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (106 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.0680

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00287503).
• BP6: Variant 16-89805388-G-A is Benign according to our data. Variant chr16-89805388-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 321367.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 16 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.601C>T	p.Pro201Ser	missense_variant	7/43	ENST00000389301.8
FANCA	NM_001286167.3	c.601C>T	p.Pro201Ser	missense_variant	7/43
FANCA	NM_001018112.3	c.601C>T	p.Pro201Ser	missense_variant	7/11
FANCA	NM_001351830.2	c.505C>T	p.Pro169Ser	missense_variant	6/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.601C>T	p.Pro201Ser	missense_variant	7/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.00443 AC: 674 AN: 152148 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0539

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00599 AC: 1490 AN: 248550 Hom.: 46 AF XY: 0.00573 AC XY: 771 AN XY: 134504

Gnomad AFR exome AF: 0.0000618

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0586

Gnomad NFE exome AF: 0.00167

Gnomad OTH exome AF: 0.00574

GnomAD4 exome AF: 0.00251 AC: 3665 AN: 1460132 Hom.: 106 Cov.: 30 AF XY: 0.00246 AC XY: 1784 AN XY: 726460

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0561

Gnomad4 NFE exome AF: 0.000475

Gnomad4 OTH exome AF: 0.00239

GnomAD4 genome AF: 0.00443 AC: 674 AN: 152266 Hom.: 16 Cov.: 32 AF XY: 0.00660 AC XY: 491 AN XY: 74440

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0539

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000758 Hom.: 1

Bravo AF: 0.000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.00531 AC: 645

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 01, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 23, 2022	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 24, 2021

- -

Fanconi anemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Fanconi anemia complementation group A Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.58
Cadd	Benign	1.9
Dann	Benign	0.75
DEOGEN2	Benign	0.082	T;.;.;T;T;.
Eigen	Benign	-0.93
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.79	T;T;T;T;T;T
MetaRNN	Benign	0.0029	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.71	N;N;N;N;N;D
REVEL	Benign	0.047
Sift	Benign	0.29	T;T;T;T;T;T
Sift4G	Benign	0.40	T;T;T;T;T;T
Polyphen		0.0020	B;.;B;.;B;B
Vest4		0.16
MVP		0.39
ClinPred		0.0099	T
GERP RS		-0.44
Varity_R		0.018
gMVP		0.080

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144917960; hg19: chr16-89871796; COSMIC: COSV101224683; COSMIC: COSV101224683;