3-184342066-G-A

Position:

• chr3-184342066-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_144635.5(FAM131A):​c.326G>A​(p.Gly109Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM131A NM_144635.5 missense, splice_region
• Scores: Splicing: ADA: 0.9969
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.49

Genes affected

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.818

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FAM131A	NM_144635.5	c.326G>A	p.Gly109Asp	missense_variant, splice_region_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.326G>A	p.Gly109Asp	missense_variant, splice_region_variant	4/6	2	NM_144635.5	ENSP00000373360.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251454 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

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 Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

Aug 29, 2024

The c.326G>A (p.G109D) 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 326, causing the glycine (G) at amino acid position 109 to be replaced by an aspartic acid (D). 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	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;.;D;D;D;D;D;T
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	.;.;.;.;.;.;.;M
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.7	D;D;D;D;.;D;D;D
REVEL	Uncertain	0.62
Sift	Pathogenic	0.0	D;D;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;.;D;D;D
Vest4		0.73
MutPred		0.65		.;.;.;.;.;.;.;Gain of solvent accessibility (P = 0.0638);
MVP		0.80
MPC		0.92
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.90
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.15		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: rs765691839; hg19: chr3-184059854; COSMIC: COSV55600609; COSMIC: COSV55600609;