X-153794580-C-G

Position:

• chrX-153794580-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001204526.1(SSR4):​c.14C>G​(p.Pro5Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,071,562 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 5/7 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000019 (0 hom. 2 hem.)
• Consequence: SSR4 NM_001204526.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0730

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SSR4	NM_001204526.1	c.14C>G	p.Pro5Arg	missense_variant	1/7		NP_001191455.1
SSR4	NM_001204527.2	c.11-94C>G		intron_variant			NP_001191456.1
SSR4	XM_047442389.1	c.68-94C>G		intron_variant			XP_047298345.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SSR4	ENST00000320857.7	c.-20C>G		5_prime_UTR_variant	1/7	2		ENSP00000317331	P1
SSR4	ENST00000370087.5	c.-14-94C>G		intron_variant		3		ENSP00000359104	P1
SSR4	ENST00000482902.5	n.132C>G		non_coding_transcript_exon_variant	1/6	2
SSR4	ENST00000491833.5	n.161-94C>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000187 AC: 2 AN: 1071562 Hom.: 0 Cov.: 31 AF XY: 0.00000573 AC XY: 2 AN XY: 349340

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: 0.00000241

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 08, 2017

The P5R variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The P5R variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The P5R variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant likely does not alter the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	8.9
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1557071630; hg19: chrX-153060035;