4-2646713-A-G

Position:

• chr4-2646713-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001366318.2(FAM193A):​c.1192A>G​(p.Ser398Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,320 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: FAM193A NM_001366318.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.44

Genes affected

FAM193A (HGNC:16822): (family with sequence similarity 193 member A)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07550615).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FAM193A	NM_001366318.2	c.1192A>G	p.Ser398Gly	missense_variant	7/21	ENST00000637812.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FAM193A	ENST00000637812.2	c.1192A>G	p.Ser398Gly	missense_variant	7/21	5	NM_001366318.2	A2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460320 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 726484

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000756

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

Jul 26, 2022

The c.319A>G (p.S107G) alteration is located in exon 5 (coding exon 3) of the FAM193A gene. This alteration results from a A to G substitution at nucleotide position 319, causing the serine (S) at amino acid position 107 to be replaced by a glycine (G). 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	Benign	0.073
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0032	.;.;.;T;.;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T;T;T;T;.
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.076	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	.;L;L;L;L;L
MutationTaster	Benign	0.97	N;N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.89	.;N;N;N;N;N
REVEL	Benign	0.062
Sift	Benign	0.034	.;D;D;D;D;D
Sift4G	Benign	0.16	.;T;T;T;D;T
Polyphen		0.0	.;.;B;B;.;.
Vest4		0.25, 0.27, 0.23, 0.22
MutPred		0.12		.;Gain of glycosylation at Y111 (P = 0.0053);Gain of glycosylation at Y111 (P = 0.0053);Gain of glycosylation at Y111 (P = 0.0053);Gain of glycosylation at Y111 (P = 0.0053);Gain of glycosylation at Y111 (P = 0.0053);
MVP		0.043
MPC		0.15
ClinPred		0.12	T
GERP RS		-0.39
Varity_R		0.040
gMVP		0.11

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: rs781076887; hg19: chr4-2648440;