rs782627156
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS1_Supporting
The NM_000117.3(EMD):c.704T>C(p.Phe235Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,210,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 24)
Exomes 𝑓: 0.0000027 ( 0 hom. 1 hem. )
Consequence
EMD
NM_000117.3 missense
NM_000117.3 missense
Scores
6
7
4
Clinical Significance
Conservation
PhyloP100: 1.73
Genes affected
EMD (HGNC:3331): (emerin) Emerin is a serine-rich nuclear membrane protein and a member of the nuclear lamina-associated protein family. It mediates membrane anchorage to the cytoskeleton. Dreifuss-Emery muscular dystrophy is an X-linked inherited degenerative myopathy resulting from mutation in the emerin gene. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -1 ACMG points.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000178 (2/112151) while in subpopulation EAS AF= 0.000558 (2/3582). AF 95% confidence interval is 0.0000983. There are 0 homozygotes in gnomad4. There are 1 alleles in male gnomad4 subpopulation. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EMD | NM_000117.3 | c.704T>C | p.Phe235Ser | missense_variant | 6/6 | ENST00000369842.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EMD | ENST00000369842.9 | c.704T>C | p.Phe235Ser | missense_variant | 6/6 | 1 | NM_000117.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000178 AC: 2AN: 112151Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1AN XY: 34319
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GnomAD3 exomes AF: 0.0000109 AC: 2AN: 182780Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 67550
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GnomAD4 exome AF: 0.00000273 AC: 3AN: 1098048Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 1AN XY: 363446
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GnomAD4 genome ? AF: 0.0000178 AC: 2AN: 112151Hom.: 0 Cov.: 24 AF XY: 0.0000291 AC XY: 1AN XY: 34319
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 02, 2018 | - - |
X-linked Emery-Dreifuss muscular dystrophy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2021 | This sequence change replaces phenylalanine with serine at codon 235 of the EMD protein (p.Phe235Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is present in population databases (rs782627156, ExAC 0.02%). This variant has not been reported in the literature in individuals affected with EMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 531734). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Benign
Dann
Uncertain
DEOGEN2
Pathogenic
D;T
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;.
Vest4
MutPred
Gain of catalytic residue at F235 (P = 0.0433);.;
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at