X-154379368-G-A

Variant names:

• chrX-154379368-G-A
• rs1364497478
• NM_000117.3:c.-117G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000117.3(EMD):​c.-117G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000915 in 753,827 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., 15 hem., cov: 26)
  • Exomes 𝑓: 0.000044 (0 hom. 10 hem.)
• Consequence: EMD NM_000117.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.311
• Publications: 0 publications found

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]

EMD Gene-Disease associations (from GenCC):

• X-linked Emery-Dreifuss muscular dystrophy

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• heart conduction disease

  Inheritance: XL Classification: STRONG Submitted by: Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant X-154379368-G-A is Benign according to our data. Variant chrX-154379368-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3057492.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000361 (41/113549) while in subpopulation AFR AF = 0.00127 (40/31412). AF 95% confidence interval is 0.00096. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EMD	NM_000117.3	c.-117G>A		5_prime_UTR_variant	Exon 1 of 6	ENST00000369842.9	NP_000108.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EMD	ENST00000369842.9	c.-117G>A		5_prime_UTR_variant	Exon 1 of 6	1	NM_000117.3	ENSP00000358857.4

Frequencies

GnomAD3 genomes AF: 0.000361 AC: 41 AN: 113502 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00128

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000437 AC: 28 AN: 640278 Hom.: 0 Cov.: 10 AF XY: 0.0000573 AC XY: 10 AN XY: 174446

African (AFR) AF: 0.000918 AC: 13 AN: 14156

American (AMR) AF: 0.000153 AC: 3 AN: 19578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13177

East Asian (EAS) AF: 0.00 AC: 0 AN: 23017

South Asian (SAS) AF: 0.00 AC: 0 AN: 35784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30227

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2075

European-Non Finnish (NFE) AF: 0.0000233 AC: 11 AN: 472207

Other (OTH) AF: 0.0000333 AC: 1 AN: 30057

GnomAD4 genome AF: 0.000361 AC: 41 AN: 113549 Hom.: 0 Cov.: 26 AF XY: 0.000420 AC XY: 15 AN XY: 35733

African (AFR) AF: 0.00127 AC: 40 AN: 31412

American (AMR) AF: 0.00 AC: 0 AN: 10957

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2661

East Asian (EAS) AF: 0.00 AC: 0 AN: 3580

South Asian (SAS) AF: 0.00 AC: 0 AN: 2857

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 216

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53262

Other (OTH) AF: 0.00 AC: 0 AN: 1550

Alfa AF: 0.000356 Hom.: 1

Bravo AF: 0.000298

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

EMD-related disorder Benign:1

May 05, 2021

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	12
DANN	Benign	0.92
PhyloP100		0.31
PromoterAI		-0.052	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs1364497478; hg19: chrX-153607728;