rs376307136

chr16-89816557-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000135.4(FANCA):c.59G>A(p.Arg20Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000204 in 1,511,088 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R20S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00022 (5 hom.)
• Consequence: FANCA NM_000135.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -0.432

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015266955).
• BP6: Variant 16-89816557-C-T is Benign according to our data. Variant chr16-89816557-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 321375.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000105 (16/152220) while in subpopulation SAS AF= 0.0029 (14/4832). AF 95% confidence interval is 0.00175. There are 1 homozygotes in gnomad4. There are 13 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FANCA	NM_000135.4	c.59G>A	p.Arg20Lys	missense_variant	1/43	ENST00000389301.8
FANCA	NM_001286167.3	c.59G>A	p.Arg20Lys	missense_variant	1/43
FANCA	NM_001018112.3	c.59G>A	p.Arg20Lys	missense_variant	1/11
FANCA	NM_001351830.2	c.59G>A	p.Arg20Lys	missense_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FANCA	ENST00000389301.8	c.59G>A	p.Arg20Lys	missense_variant	1/43	1	NM_000135.4	P1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152112 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00289

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000576 AC: 62 AN: 107622 Hom.: 2 AF XY: 0.000629 AC XY: 38 AN XY: 60402

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000693

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000726

Gnomad OTH exome AF: 0.000629

GnomAD4 exome AF: 0.000216 AC: 293 AN: 1358868 Hom.: 5 Cov.: 31 AF XY: 0.000291 AC XY: 195 AN XY: 670852

Gnomad4 AFR exome AF: 0.0000360

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000743

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00293

Gnomad4 FIN exome AF: 0.0000896

Gnomad4 NFE exome AF: 0.0000243

Gnomad4 OTH exome AF: 0.000318

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152220 Hom.: 1 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74430

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000235 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000359 AC: 33

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fanconi anemia Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 26, 2020	- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	13
Dann	Benign	0.82
DEOGEN2	Benign	0.10	T;.;.;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.59	T;T;T;T;T;T
M_CAP	Pathogenic	0.59	D
MetaRNN	Benign	0.015	T;T;T;T;T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.1	L;L;L;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N
REVEL	Benign	0.061
Sift	Benign	0.21	T;T;T;T;T;T
Sift4G	Benign	0.15	T;T;T;T;T;D
Polyphen		0.40	B;.;.;.;B;B
Vest4		0.19
MutPred		0.25		Gain of catalytic residue at R20 (P = 0.0174);Gain of catalytic residue at R20 (P = 0.0174);Gain of catalytic residue at R20 (P = 0.0174);Gain of catalytic residue at R20 (P = 0.0174);Gain of catalytic residue at R20 (P = 0.0174);Gain of catalytic residue at R20 (P = 0.0174);
MVP		0.88
ClinPred		0.015	T
GERP RS		-1.6
Varity_R		0.070
gMVP		0.15

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: rs376307136; hg19: chr16-89882965;