X-154380364-C-T

Variant names:

• chrX-154380364-C-T
• rs145985318
• NM_000117.3:c.396C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000117.3(EMD):​c.396C>T​(p.His132His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,210,227 control chromosomes in the GnomAD database, including 1 homozygotes. There are 509 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00076 (0 hom., 28 hem., cov: 24)
  • Exomes 𝑓: 0.0014 (1 hom. 481 hem.)
• Consequence: EMD NM_000117.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.154
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-154380364-C-T is Benign according to our data. Variant chrX-154380364-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 42273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.154 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000762 (86/112871) while in subpopulation NFE AF = 0.00113 (60/53251). AF 95% confidence interval is 0.000898. There are 0 homozygotes in GnomAd4. There are 28 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 28 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000117.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	NM_000117.3	MANE Select	c.396C>T	p.His132His	synonymous	Exon 4 of 6	NP_000108.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EMD	ENST00000369842.9	TSL:1 MANE Select	c.396C>T	p.His132His	synonymous	Exon 4 of 6	ENSP00000358857.4
	EMD	ENST00000933532.1		c.396C>T	p.His132His	synonymous	Exon 4 of 6	ENSP00000603591.1
	EMD	ENST00000933533.1		c.420C>T	p.His140His	synonymous	Exon 4 of 6	ENSP00000603592.1

Frequencies

GnomAD3 genomes AF: 0.000762 AC: 86 AN: 112817 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000279

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.000277

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000779 AC: 142 AN: 182290 AF XY: 0.000813

Gnomad AFR exome AF: 0.000153

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.000538

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00219

Gnomad NFE exome AF: 0.00114

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00144 AC: 1575 AN: 1097356 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 481 AN XY: 363252

African (AFR) AF: 0.000189 AC: 5 AN: 26402

American (AMR) AF: 0.000312 AC: 11 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.000361 AC: 7 AN: 19385

East Asian (EAS) AF: 0.00 AC: 0 AN: 30204

South Asian (SAS) AF: 0.0000739 AC: 4 AN: 54138

European-Finnish (FIN) AF: 0.00234 AC: 93 AN: 39694

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4137

European-Non Finnish (NFE) AF: 0.00165 AC: 1391 AN: 842109

Other (OTH) AF: 0.00139 AC: 64 AN: 46083

GnomAD4 genome AF: 0.000762 AC: 86 AN: 112871 Hom.: 0 Cov.: 24 AF XY: 0.000799 AC XY: 28 AN XY: 35027

African (AFR) AF: 0.000193 AC: 6 AN: 31122

American (AMR) AF: 0.000279 AC: 3 AN: 10760

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2651

East Asian (EAS) AF: 0.000278 AC: 1 AN: 3597

South Asian (SAS) AF: 0.00 AC: 0 AN: 2767

European-Finnish (FIN) AF: 0.00207 AC: 13 AN: 6270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00113 AC: 60 AN: 53251

Other (OTH) AF: 0.00 AC: 0 AN: 1549

Alfa AF: 0.000509 Hom.: 4

Bravo AF: 0.000608

EpiCase AF: 0.00136

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	X-linked Emery-Dreifuss muscular dystrophy (2)
-	-	1	Cardiomyopathy (1)
-	-	1	Cardiovascular phenotype (1)
-	-	1	EMD-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.5
DANN	Benign	0.77
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs145985318; hg19: chrX-153608724; COSMIC: COSV63962157; COSMIC: COSV63962157;