X-153794541-A-C

Variant names:

• chrX-153794541-A-C
• rs112969179
• NM_001204526.1:c.-26A>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_001204526.1(SSR4):​c.-26A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000503 in 1,168,137 control chromosomes in the GnomAD database, including 6 homozygotes. There are 147 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., 96 hem., cov: 26)
  • Exomes 𝑓: 0.00024 (3 hom. 51 hem.)
• Consequence: SSR4 NM_001204526.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.96

Genes affected

SSR4 (HGNC:11326): (signal sequence receptor subunit 4) This gene encodes the delta subunit of the translocon-associated protein complex which is involved in translocating proteins across the endoplasmic reticulum membrane. The encoded protein is located in the Xq28 region and is arranged in a compact head-to-head manner with the isocitrate dehydrogenase 3 (NAD+) gamma gene and both genes are driven by a CpG-embedded bidirectional promoter. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2011]

IDH3G (HGNC:5386): (isocitrate dehydrogenase (NAD(+)) 3 non-catalytic subunit gamma) Isocitrate dehydrogenases catalyze the oxidative decarboxylation of isocitrate to 2-oxoglutarate. These enzymes belong to two distinct subclasses, one of which utilizes NAD(+) as the electron acceptor and the other NADP(+). Five isocitrate dehydrogenases have been reported: three NAD(+)-dependent isocitrate dehydrogenases, which localize to the mitochondrial matrix, and two NADP(+)-dependent isocitrate dehydrogenases, one of which is mitochondrial and the other predominantly cytosolic. NAD(+)-dependent isocitrate dehydrogenases catalyze the allosterically regulated rate-limiting step of the tricarboxylic acid cycle. Each isozyme is a heterotetramer that is composed of two alpha subunits, one beta subunit, and one gamma subunit. The protein encoded by this gene is the gamma subunit of one isozyme of NAD(+)-dependent isocitrate dehydrogenase. This gene is a candidate gene for periventricular heterotopia. Several alternatively spliced transcript variants of this gene have been described, but only some of their full length natures have been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-153794541-A-C is Benign according to our data. Variant chrX-153794541-A-C is described in ClinVar as [Benign]. Clinvar id is 510069.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SSR4	NM_001204526.1	c.-26A>C		5_prime_UTR_variant	Exon 1 of 7		NP_001191455.1
SSR4	NM_001204527.2	c.11-133A>C		intron_variant	Intron 1 of 6		NP_001191456.1
SSR4	XM_047442389.1	c.68-133A>C		intron_variant	Intron 1 of 6		XP_047298345.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SSR4	ENST00000320857	c.-59A>C		5_prime_UTR_variant	Exon 1 of 7	2		ENSP00000317331.3
SSR4	ENST00000370087.5	c.-14-133A>C		intron_variant	Intron 1 of 6	3		ENSP00000359104.1
SSR4	ENST00000482902.5	n.93A>C		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes AF: 0.00295 AC: 334 AN: 113298 Hom.: 3 Cov.: 26 AF XY: 0.00271 AC XY: 96 AN XY: 35448

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000551

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

GnomAD3 exomes AF: 0.000686 AC: 79 AN: 115236 Hom.: 0 AF XY: 0.000300 AC XY: 12 AN XY: 40020

Gnomad AFR exome AF: 0.0103

Gnomad AMR exome AF: 0.000305

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000243 AC: 256 AN: 1054786 Hom.: 3 Cov.: 31 AF XY: 0.000148 AC XY: 51 AN XY: 344392

Gnomad4 AFR exome AF: 0.00927

Gnomad4 AMR exome AF: 0.000356

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: 0.00000366

Gnomad4 OTH exome AF: 0.000225

GnomAD4 genome AF: 0.00293 AC: 332 AN: 113351 Hom.: 3 Cov.: 26 AF XY: 0.00270 AC XY: 96 AN XY: 35511

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00178 Hom.: 10

Bravo AF: 0.00334

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 07, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	15
DANN	Benign	0.85

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: rs112969179; hg19: chrX-153059996;