5-154002270-T-C

Variant names:

• chr5-154002270-T-C
• rs761751709
• NM_018691.4:c.1237A>G

Variant summary

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

The NM_018691.4(FAM114A2):​c.1237A>G​(p.Arg413Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: FAM114A2 NM_018691.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.63

Genes affected

FAM114A2 (HGNC:1333): (family with sequence similarity 114 member A2)

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 rank	MANE	Protein	UniProt
FAM114A2	NM_018691.4	c.1237A>G	p.Arg413Gly	missense_variant	Exon 11 of 14	ENST00000351797.9	NP_061161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FAM114A2	ENST00000351797.9	c.1237A>G	p.Arg413Gly	missense_variant	Exon 11 of 14	1	NM_018691.4	ENSP00000341597.4
FAM114A2	ENST00000520667.5	c.1237A>G	p.Arg413Gly	missense_variant	Exon 12 of 15	1		ENSP00000430384.1
FAM114A2	ENST00000522858.5	c.1237A>G	p.Arg413Gly	missense_variant	Exon 11 of 14	1		ENSP00000430489.1
FAM114A2	ENST00000520313.5	c.1027A>G	p.Arg343Gly	missense_variant	Exon 10 of 13	2		ENSP00000429088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251122 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135686

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

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

Aug 04, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1237A>G (p.R413G) alteration is located in exon 11 (coding exon 10) of the FAM114A2 gene. This alteration results from a A to G substitution at nucleotide position 1237, causing the arginine (R) at amino acid position 413 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	0.29
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T;T;T;T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.86	.;.;D;D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M;M;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.011	D;D;D;D
Sift4G	Uncertain	0.015	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.79
MutPred		0.33		Loss of stability (P = 0.1395);Loss of stability (P = 0.1395);Loss of stability (P = 0.1395);.;
MVP		0.25
MPC		0.17
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.31
gMVP		0.49

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: rs761751709; hg19: chr5-153381830;