6-11104715-G-A

Variant names:

• chr6-11104715-G-A
• rs1758057157
• NM_207582.3:c.596C>T

Variant summary

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

The NM_207582.3(ERVFRD-1):​c.596C>T​(p.Ser199Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ERVFRD-1 NM_207582.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.365

Genes affected

ERVFRD-1 (HGNC:33823): (endogenous retrovirus group FRD member 1, envelope) Many different human endogenous retrovirus (HERV) families are expressed in normal placental tissue at high levels, suggesting that HERVs are functionally important in reproduction. This gene is part of a human endogenous retrovirus provirus on chromosome 6 that has inactivating mutations in the gag and pol genes. This gene is the envelope glycoprotein gene which appears to have been selectively preserved. The gene's protein product plays a major role in placental development and trophoblast fusion. The protein has the characteristics of a typical retroviral envelope protein, including a cleavage site that separates the surface (SU) and transmembrane (TM) proteins which form a heterodimer. [provided by RefSeq, Jun 2012]

SMIM13 (HGNC:27356): (small integral membrane protein 13) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

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=0.103979886).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERVFRD-1	NM_207582.3	c.596C>T	p.Ser199Leu	missense_variant	Exon 2 of 2	ENST00000472091.2	NP_997465.1
SMIM13	NM_001135575.2	c.76+10326G>A		intron_variant	Intron 1 of 1	ENST00000416247.4	NP_001129047.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERVFRD-1	ENST00000472091.2	c.596C>T	p.Ser199Leu	missense_variant	Exon 2 of 2	1	NM_207582.3	ENSP00000420174.1
SMIM13	ENST00000416247.4	c.76+10326G>A		intron_variant	Intron 1 of 1	1	NM_001135575.2	ENSP00000451866.1
ERVFRD-1	ENST00000542862.1	c.596C>T	p.Ser199Leu	missense_variant	Exon 1 of 1	6
SMIM13	ENST00000376935.4	n.76+10326G>A		intron_variant	Intron 1 of 2	5		ENSP00000452219.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.596C>T (p.S199L) alteration is located in exon 2 (coding exon 1) of the ERVFRD-1 gene. This alteration results from a C to T substitution at nucleotide position 596, causing the serine (S) at amino acid position 199 to be replaced by a leucine (L). 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	0.15
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Benign	0.016	T;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.0064	N
LIST_S2	Benign	0.61	.;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.98	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.19	N;N
REVEL	Benign	0.021
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.10	T;T
Polyphen		0.62	P;P
Vest4		0.22
MutPred		0.52		Loss of disorder (P = 0.0127);Loss of disorder (P = 0.0127);
MVP		0.14
MPC		0.39
ClinPred		0.17	T
GERP RS		0.23
Varity_R		0.13
gMVP		0.060

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: rs1758057157; hg19: chr6-11104948;