chr3-184342224-G-A

Position:

• chr3-184342224-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_144635.5(FAM131A):​c.484G>A​(p.Glu162Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: FAM131A NM_144635.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.01

Genes affected

FAM131A (HGNC:28308): (family with sequence similarity 131 member A)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM131A	NM_144635.5	c.484G>A	p.Glu162Lys	missense_variant	4/6	ENST00000383847.7	NP_653236.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FAM131A	ENST00000383847.7	c.484G>A	p.Glu162Lys	missense_variant	4/6	2	NM_144635.5	ENSP00000373360	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249574 Hom.: 0 AF XY: 0.00000741 AC XY: 1 AN XY: 134886

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1455740 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 722940

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 27, 2022

The c.484G>A (p.E162K) alteration is located in exon 4 (coding exon 4) of the FAM131A gene. This alteration results from a G to A substitution at nucleotide position 484, causing the glutamic acid (E) at amino acid position 162 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	29
DANN	Uncertain	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	.;D;.;D;D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.53	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;.;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.5	D;N;D;D;D;.;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0060	D;D;D;D;D;.;D;D;D
Sift4G	Benign	0.072	T;D;T;D;D;.;D;T;T
Polyphen		0.98	.;D;.;.;.;.;.;.;.
Vest4		0.82
MutPred		0.20		.;.;.;.;.;.;.;.;Gain of ubiquitination at E131 (P = 0.0075);
MVP		0.66
MPC		0.50
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.58
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs754589250; hg19: chr3-184060012;