NM_001047.4:c.-176C>T

Variant names:

• chr5-6633401-C-T
• rs8192127
• ENST00000854430.1:c.-176C>T

Variant summary

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

The NM_001047.4(SRD5A1):​c.-176C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00188 in 756,254 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0069 (8 hom., cov: 34)
  • Exomes 𝑓: 0.00062 (5 hom.)
• Consequence: SRD5A1 NM_001047.4 upstream_gene
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.62
• Publications: 1 publications found

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]

NSUN2 Gene-Disease associations (from GenCC):

• syndromic intellectual disability

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal recessive 5

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Dubowitz syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• RASopathy

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 5-6633401-C-T is Benign according to our data. Variant chr5-6633401-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1190785.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00687 (1046/152274) while in subpopulation AFR AF = 0.0243 (1010/41566). AF 95% confidence interval is 0.0231. There are 8 homozygotes in GnomAd4. There are 489 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001047.4. 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
	SRD5A1	NM_001047.4	MANE Select	c.-176C>T		upstream_gene	N/A	NP_001038.1	P18405
	SRD5A1	NM_001324322.2		c.-150C>T		upstream_gene	N/A	NP_001311251.1
	SRD5A1	NM_001324323.2		c.-897C>T		upstream_gene	N/A	NP_001311252.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SRD5A1	ENST00000854430.1		c.-176C>T		5_prime_UTR	Exon 1 of 4	ENSP00000524489.1
	SRD5A1	ENST00000510531.6	TSL:2	n.-176C>T		non_coding_transcript_exon	Exon 1 of 6	ENSP00000425330.1	D6RDL6
	SRD5A1	ENST00000510531.6	TSL:2	n.-176C>T		5_prime_UTR	Exon 1 of 6	ENSP00000425330.1	D6RDL6

Frequencies

GnomAD3 genomes AF: 0.00687 AC: 1045 AN: 152162 Hom.: 8 Cov.: 34

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD4 exome AF: 0.000624 AC: 377 AN: 603980 Hom.: 5 Cov.: 8 AF XY: 0.000496 AC XY: 151 AN XY: 304142

African (AFR) AF: 0.0260 AC: 309 AN: 11888

American (AMR) AF: 0.00141 AC: 12 AN: 8502

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12952

East Asian (EAS) AF: 0.00 AC: 0 AN: 24664

South Asian (SAS) AF: 0.000137 AC: 5 AN: 36396

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28780

Middle Eastern (MID) AF: 0.000448 AC: 1 AN: 2230

European-Non Finnish (NFE) AF: 0.0000134 AC: 6 AN: 448686

Other (OTH) AF: 0.00147 AC: 44 AN: 29882

GnomAD4 genome AF: 0.00687 AC: 1046 AN: 152274 Hom.: 8 Cov.: 34 AF XY: 0.00657 AC XY: 489 AN XY: 74462

African (AFR) AF: 0.0243 AC: 1010 AN: 41566

American (AMR) AF: 0.00157 AC: 24 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67990

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00691 Hom.: 2

Bravo AF: 0.00801

Asia WGS AF: 0.00289 AC: 10 AN: 3474

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	-0.74
CADD	Benign	5.5
DANN	Benign	0.92
PhyloP100		-1.6
PromoterAI		-0.18	Neutral
Mutation Taster		=300/0	polymorphism

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

Other links and lift over

dbSNP: rs8192127; hg19: chr5-6633514; COSMIC: COSV52955321; COSMIC: COSV52955321;