6-11104610-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_207582.3(ERVFRD-1):​c.701G>A​(p.Arg234Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000167 in 1,613,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ERVFRD-1
NM_207582.3 missense

Scores

2
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.305
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.17247128).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERVFRD-1NM_207582.3 linkc.701G>A p.Arg234Gln missense_variant Exon 2 of 2 ENST00000472091.2 NP_997465.1 P60508
SMIM13NM_001135575.2 linkc.76+10221C>T intron_variant Intron 1 of 1 ENST00000416247.4 NP_001129047.1 P0DJ93

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ERVFRD-1ENST00000472091.2 linkc.701G>A p.Arg234Gln missense_variant Exon 2 of 2 1 NM_207582.3 ENSP00000420174.1 P60508
SMIM13ENST00000416247.4 linkc.76+10221C>T intron_variant Intron 1 of 1 1 NM_001135575.2 ENSP00000451866.1 P0DJ93
ERVFRD-1ENST00000542862.1 linkc.701G>A p.Arg234Gln missense_variant Exon 1 of 1 6 P60508
SMIM13ENST00000376935.4 linkn.76+10221C>T intron_variant Intron 1 of 2 5 ENSP00000452219.1 P0DJ93

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152112
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000121
AC:
3
AN:
248400
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134592
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.00000901
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461858
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
8
AN XY:
727232
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152112
Hom.:
0
Cov.:
32
AF XY:
0.0000404
AC XY:
3
AN XY:
74308
show subpopulations
Gnomad4 AFR
AF:
0.0000483
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000227
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 23, 2021
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.701G>A (p.R234Q) alteration is located in exon 2 (coding exon 1) of the ERVFRD-1 gene. This alteration results from a G to A substitution at nucleotide position 701, causing the arginine (R) at amino acid position 234 to be replaced by a glutamine (Q). 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
-0.33
T
BayesDel_noAF
Benign
-0.63
CADD
Benign
19
DANN
Uncertain
1.0
DEOGEN2
Benign
0.027
T;T
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.34
FATHMM_MKL
Benign
0.058
N
LIST_S2
Benign
0.61
.;T
M_CAP
Benign
0.0026
T
MetaRNN
Benign
0.17
T;T
MetaSVM
Benign
-1.0
T
PrimateAI
Benign
0.39
T
PROVEAN
Benign
0.33
N;N
REVEL
Benign
0.070
Sift
Benign
0.14
T;T
Sift4G
Uncertain
0.033
D;D
Polyphen
0.99
D;D
Vest4
0.12
MutPred
0.46
Gain of sheet (P = 0.1208);Gain of sheet (P = 0.1208);
MVP
0.15
MPC
1.2
ClinPred
0.53
D
GERP RS
0.23
Varity_R
0.11
gMVP
0.098

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs756242354; hg19: chr6-11104843; COSMIC: COSV65368765; API