5-6633321-G-A

Variant names:

• chr5-6633321-G-A
• rs569790049
• NM_001047.4:c.-256G>A

Variant summary

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

The NM_001047.4(SRD5A1):​c.-256G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 511,458 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0044 (8 hom.)
• Consequence: SRD5A1 NM_001047.4 upstream_gene
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.657

Genes affected

SRD5A1 (HGNC:11284): (steroid 5 alpha-reductase 1) Steroid 5-alpha-reductase (EC 1.3.99.5) catalyzes the conversion of testosterone into the more potent androgen, dihydrotestosterone (DHT). Also see SRD5A2 (MIM 607306).[supplied by OMIM, Mar 2008]

NSUN2 (HGNC:25994): (NOP2/Sun RNA methyltransferase 2) This gene encodes a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA(Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BS2: High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SRD5A1	NM_001047.4	c.-256G>A		upstream_gene_variant		ENST00000274192.7	NP_001038.1
SRD5A1	NM_001324322.2	c.-230G>A		upstream_gene_variant			NP_001311251.1
SRD5A1	NM_001324323.2	c.-977G>A		upstream_gene_variant			NP_001311252.1
SRD5A1	NR_136739.2	n.-119G>A		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SRD5A1	ENST00000274192.7	c.-256G>A		upstream_gene_variant		1	NM_001047.4	ENSP00000274192.5

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152202 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00329

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00441 AC: 1583 AN: 359140 Hom.: 8 Cov.: 4 AF XY: 0.00418 AC XY: 780 AN XY: 186590

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.00248

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.0000431

Gnomad4 SAS exome AF: 0.00235

Gnomad4 FIN exome AF: 0.00503

Gnomad4 NFE exome AF: 0.00544

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152318 Hom.: 1 Cov.: 34 AF XY: 0.00311 AC XY: 232 AN XY: 74480

Gnomad4 AFR AF: 0.00118

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00269

Gnomad4 FIN AF: 0.00329

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00371 Hom.: 0

Bravo AF: 0.00328

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual Disability, Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.3
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs569790049; hg19: chr5-6633434;