rs1557182365

chrX-154379983-C-T

Variant summary

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

The NM_000117.3(EMD):c.229C>T(p.Pro77Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000364 in 1,097,979 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. P77P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0000036 (0 hom. 1 hem.)
• Consequence: EMD NM_000117.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.91

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]

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/exons	MANE	UniProt
EMD	NM_000117.3	c.229C>T	p.Pro77Ser	missense_variant	3/6	ENST00000369842.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EMD	ENST00000369842.9	c.229C>T	p.Pro77Ser	missense_variant	3/6	1	NM_000117.3	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 0.00000364 AC: 4 AN: 1097979 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363375

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000475

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

May 05, 2016

- -

X-linked Emery-Dreifuss muscular dystrophy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 15, 2020

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. 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with EMD-related conditions. ClinVar contains an entry for this variant (Variation ID: 435058). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 77 of the EMD protein (p.Pro77Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;T
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T;T
M_CAP	Uncertain	0.27	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	0.56	D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.012	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.36
MutPred		0.41		Gain of phosphorylation at P77 (P = 0.0389);.;
MVP		0.86
MPC		0.94
ClinPred		0.92	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.22
gMVP		0.57

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: rs1557182365; hg19: chrX-153608343;