6-11105258-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.53G>A​(p.Arg18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000353 in 1,613,874 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

ERVFRD-1
NM_207582.3 missense

Scores

1
17

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=0.07205734).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ERVFRD-1NM_207582.3 linkc.53G>A p.Arg18His missense_variant Exon 2 of 2 ENST00000472091.2 NP_997465.1 P60508
SMIM13NM_001135575.2 linkc.76+10869C>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.53G>A p.Arg18His missense_variant Exon 2 of 2 1 NM_207582.3 ENSP00000420174.1 P60508
SMIM13ENST00000416247.4 linkc.76+10869C>T intron_variant Intron 1 of 1 1 NM_001135575.2 ENSP00000451866.1 P0DJ93
ERVFRD-1ENST00000542862.1 linkc.53G>A p.Arg18His missense_variant Exon 1 of 1 6 P60508
SMIM13ENST00000376935.4 linkn.76+10869C>T intron_variant Intron 1 of 2 5 ENSP00000452219.1 P0DJ93

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152034
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000398
AC:
10
AN:
251030
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135664
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.000261
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000881
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000383
AC:
56
AN:
1461840
Hom.:
0
Cov.:
32
AF XY:
0.0000468
AC XY:
34
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.000290
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000243
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152034
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74230
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000386
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.0000330
AC:
4

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 15, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.53G>A (p.R18H) 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 53, causing the arginine (R) at amino acid position 18 to be replaced by a histidine (H). 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
0.11
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.64
CADD
Benign
12
DANN
Uncertain
0.98
DEOGEN2
Benign
0.016
T;T
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.76
FATHMM_MKL
Benign
0.018
N
LIST_S2
Benign
0.57
.;T
M_CAP
Benign
0.0023
T
MetaRNN
Benign
0.072
T;T
MetaSVM
Benign
-0.95
T
PrimateAI
Benign
0.44
T
PROVEAN
Benign
0.20
N;N
REVEL
Benign
0.038
Sift
Benign
0.039
D;D
Sift4G
Benign
0.071
T;T
Polyphen
0.80
P;P
Vest4
0.12
MutPred
0.42
Loss of helix (P = 0.0376);Loss of helix (P = 0.0376);
MVP
0.11
MPC
0.52
ClinPred
0.058
T
GERP RS
0.23
Varity_R
0.088
gMVP
0.14

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: rs768463887; hg19: chr6-11105491; COSMIC: COSV65369528; API