chr4-55359410-CAA-TGAGTAAGGC

Variant names:

• chr4-55359410-CAA-TGAGTAAGGC
• rs587776521
• NM_024592.5:c.286_288delCAAinsTGAGTAAGGC

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_024592.5(SRD5A3):​c.286_288delCAAinsTGAGTAAGGC​(p.Gln96fs) variant causes a frameshift, stop gained change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SRD5A3 NM_024592.5 frameshift, stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.83
• Publications: 0 publications found

Genes affected

SRD5A3 (HGNC:25812): (steroid 5 alpha-reductase 3) The protein encoded by this gene belongs to the steroid 5-alpha reductase family, and polyprenol reductase subfamily. It is involved in the production of androgen 5-alpha-dihydrotestosterone (DHT) from testosterone, and maintenance of the androgen-androgen receptor activation pathway. This protein is also necessary for the conversion of polyprenol into dolichol, which is required for the synthesis of dolichol-linked monosaccharides and the oligosaccharide precursor used for N-linked glycosylation of proteins. Mutations in this gene are associated with congenital disorder of glycosylation type Iq. [provided by RefSeq, Mar 2011]

SRD5A3 Gene-Disease associations (from GenCC):

• SRD5A3-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ENSG00000288695 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-55359410-CAA-TGAGTAAGGC is Pathogenic according to our data. Variant chr4-55359410-CAA-TGAGTAAGGC is described in ClinVar as [Pathogenic]. Clinvar id is 18404.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A3	NM_024592.5	c.286_288delCAAinsTGAGTAAGGC	p.Gln96fs	frameshift_variant, stop_gained	Exon 2 of 5	ENST00000264228.9	NP_078868.1
SRD5A3	NM_001410732.1	c.286_288delCAAinsTGAGTAAGGC	p.Gln96fs	frameshift_variant, stop_gained	Exon 2 of 4		NP_001397661.1
SRD5A3	XM_017008601.2	c.151_153delCAAinsTGAGTAAGGC	p.Gln51fs	frameshift_variant, stop_gained	Exon 2 of 5		XP_016864090.1
SRD5A3	XM_005265767.4	c.286_288delCAAinsTGAGTAAGGC	p.Gln96fs	frameshift_variant, stop_gained	Exon 2 of 3		XP_005265824.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A3	ENST00000264228.9	c.286_288delCAAinsTGAGTAAGGC	p.Gln96fs	frameshift_variant, stop_gained	Exon 2 of 5	1	NM_024592.5	ENSP00000264228.4
ENSG00000288695	ENST00000679707.1	c.286_288delCAAinsTGAGTAAGGC	p.Gln96fs	frameshift_variant, stop_gained	Exon 2 of 6			ENSP00000505713.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

SRD5A3-congenital disorder of glycosylation Pathogenic:1

Jul 23, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Kahrizi syndrome Pathogenic:1

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PVS1,PM2,PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=17/183	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs587776521; hg19: chr4-56225577;