X-153796262-T-C

Variant names:

• chrX-153796262-T-C
• rs150497073
• NM_006280.3:c.68-172T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006280.3(SSR4):​c.68-172T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 432,172 control chromosomes in the GnomAD database, including 38 homozygotes. There are 2,048 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 0.014 (14 hom., 461 hem., cov: 25)
  • Exomes 𝑓: 0.016 (24 hom. 1587 hem.)
• Consequence: SSR4 NM_006280.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.567
• Publications: 0 publications found

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]

SSR4 Gene-Disease associations (from GenCC):

• SSR4-congenital disorder of glycosylation

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant X-153796262-T-C is Benign according to our data. Variant chrX-153796262-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1706820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0138 (1555/112794) while in subpopulation NFE AF = 0.02 (1065/53291). AF 95% confidence interval is 0.019. There are 14 homozygotes in GnomAd4. There are 461 alleles in the male GnomAd4 subpopulation. Median coverage is 25. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006280.3. 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
	SSR4	NM_006280.3	MANE Select	c.68-172T>C		intron	N/A	NP_006271.1	P51571
	SSR4	NM_001440795.1		c.149-172T>C		intron	N/A	NP_001427724.1
	SSR4	NM_001204526.2		c.101-172T>C		intron	N/A	NP_001191455.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SSR4	ENST00000370086.8	TSL:1 MANE Select	c.68-172T>C		intron	N/A	ENSP00000359103.3	P51571
	SSR4	ENST00000320857.7	TSL:2	c.68-172T>C		intron	N/A	ENSP00000317331.3	P51571
	SSR4	ENST00000370087.5	TSL:3	c.68-172T>C		intron	N/A	ENSP00000359104.1	P51571

Frequencies

GnomAD3 genomes AF: 0.0138 AC: 1555 AN: 112740 Hom.: 14 Cov.: 25

Gnomad AFR AF: 0.00283

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.00654

Gnomad ASJ AF: 0.0162

Gnomad EAS AF: 0.000554

Gnomad SAS AF: 0.00254

Gnomad FIN AF: 0.0199

Gnomad MID AF: 0.00840

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0159 AC: 5072 AN: 319378 Hom.: 24 Cov.: 4 AF XY: 0.0153 AC XY: 1587 AN XY: 104028

African (AFR) AF: 0.00290 AC: 28 AN: 9661

American (AMR) AF: 0.00581 AC: 82 AN: 14110

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 141 AN: 9673

East Asian (EAS) AF: 0.00 AC: 0 AN: 22676

South Asian (SAS) AF: 0.00548 AC: 142 AN: 25902

European-Finnish (FIN) AF: 0.0261 AC: 583 AN: 22312

Middle Eastern (MID) AF: 0.0179 AC: 27 AN: 1505

European-Non Finnish (NFE) AF: 0.0193 AC: 3750 AN: 194269

Other (OTH) AF: 0.0166 AC: 319 AN: 19270

GnomAD4 genome AF: 0.0138 AC: 1555 AN: 112794 Hom.: 14 Cov.: 25 AF XY: 0.0132 AC XY: 461 AN XY: 34950

African (AFR) AF: 0.00283 AC: 88 AN: 31119

American (AMR) AF: 0.00653 AC: 70 AN: 10712

Ashkenazi Jewish (ASJ) AF: 0.0162 AC: 43 AN: 2653

East Asian (EAS) AF: 0.000555 AC: 2 AN: 3602

South Asian (SAS) AF: 0.00255 AC: 7 AN: 2746

European-Finnish (FIN) AF: 0.0199 AC: 124 AN: 6239

Middle Eastern (MID) AF: 0.00922 AC: 2 AN: 217

European-Non Finnish (NFE) AF: 0.0200 AC: 1065 AN: 53291

Other (OTH) AF: 0.0104 AC: 16 AN: 1537

Alfa AF: 0.0160 Hom.: 89

Bravo AF: 0.0135

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.3
DANN	Benign	0.84
PhyloP100		0.57
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs150497073; hg19: chrX-153061717;