chr14-24291558-G-A

Variant names:

• chr14-24291558-G-A
• rs10134537
• NM_001136050.3:c.722C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 2P and 8B. PP3_Moderate BA1

The NM_001136050.3(DHRS1):​c.722C>T​(p.Thr241Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0683 in 1,613,984 control chromosomes in the GnomAD database, including 4,223 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: 𝑓 0.085 (611 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3612 hom.)
• Consequence: DHRS1 NM_001136050.3 missense, splice_region
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80
• Publications: 47 publications found

Genes affected

DHRS1 (HGNC:16445): (dehydrogenase/reductase 1) This gene encodes a member of the short-chain dehydrogenases/reductases (SDR) family. The encoded enzyme contains a conserved catalytic domain and likely functions as an oxidoreductase. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Nov 2008]

NOP9 (HGNC:19826): (NOP9 nucleolar protein) Enables RNA binding activity. Predicted to be involved in ribosome biogenesis. Predicted to be part of 90S preribosome and preribosome, small subunit precursor. Predicted to be active in nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000288044 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001136050.3. 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
	DHRS1	NM_001136050.3	MANE Select	c.722C>T	p.Thr241Ile	missense splice_region	Exon 7 of 9	NP_001129522.1	Q96LJ7
	DHRS1	NM_138452.3		c.722C>T	p.Thr241Ile	missense splice_region	Exon 7 of 9	NP_612461.1	Q96LJ7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHRS1	ENST00000288111.12	TSL:1 MANE Select	c.722C>T	p.Thr241Ile	missense splice_region	Exon 7 of 9	ENSP00000288111.7	Q96LJ7
	DHRS1	ENST00000561281.4	TSL:1	n.364C>T		non_coding_transcript_exon	Exon 1 of 2
	DHRS1	ENST00000396813.5	TSL:2	c.722C>T	p.Thr241Ile	missense splice_region	Exon 7 of 9	ENSP00000380027.1	Q96LJ7

Frequencies

GnomAD3 genomes AF: 0.0853 AC: 12982 AN: 152116 Hom.: 611 Cov.: 32

Gnomad AFR AF: 0.130

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.0652

Gnomad ASJ AF: 0.102

Gnomad EAS AF: 0.0746

Gnomad SAS AF: 0.0953

Gnomad FIN AF: 0.0535

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0670

Gnomad OTH AF: 0.0756

GnomAD2 exomes AF: 0.0754 AC: 18951 AN: 251492 AF XY: 0.0768

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.0623

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.0838

Gnomad FIN exome AF: 0.0516

Gnomad NFE exome AF: 0.0649

Gnomad OTH exome AF: 0.0752

GnomAD4 exome AF: 0.0665 AC: 97237 AN: 1461750 Hom.: 3612 Cov.: 31 AF XY: 0.0682 AC XY: 49594 AN XY: 727190

African (AFR) AF: 0.130 AC: 4352 AN: 33474

American (AMR) AF: 0.0647 AC: 2894 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 2871 AN: 26136

East Asian (EAS) AF: 0.0605 AC: 2400 AN: 39698

South Asian (SAS) AF: 0.100 AC: 8658 AN: 86258

European-Finnish (FIN) AF: 0.0510 AC: 2724 AN: 53418

Middle Eastern (MID) AF: 0.0923 AC: 532 AN: 5766

European-Non Finnish (NFE) AF: 0.0616 AC: 68527 AN: 1111886

Other (OTH) AF: 0.0709 AC: 4279 AN: 60390

GnomAD4 genome AF: 0.0853 AC: 12988 AN: 152234 Hom.: 611 Cov.: 32 AF XY: 0.0850 AC XY: 6331 AN XY: 74458

African (AFR) AF: 0.130 AC: 5385 AN: 41514

American (AMR) AF: 0.0653 AC: 999 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.102 AC: 355 AN: 3468

East Asian (EAS) AF: 0.0744 AC: 386 AN: 5188

South Asian (SAS) AF: 0.0956 AC: 461 AN: 4824

European-Finnish (FIN) AF: 0.0535 AC: 568 AN: 10616

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0670 AC: 4554 AN: 68014

Other (OTH) AF: 0.0748 AC: 158 AN: 2112

Alfa AF: 0.0751 Hom.: 1602

Bravo AF: 0.0866

TwinsUK AF: 0.0529 AC: 196

ALSPAC AF: 0.0599 AC: 231

ESP6500AA AF: 0.124 AC: 545

ESP6500EA AF: 0.0700 AC: 602

ExAC AF: 0.0759 AC: 9209

Asia WGS AF: 0.0750 AC: 259 AN: 3478

EpiCase AF: 0.0707

EpiControl AF: 0.0670

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.93	D
MetaRNN	Benign	0.0026	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		3.8
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.38
Sift	Benign	0.065	T
Sift4G	Benign	0.16	T
Polyphen		0.34	B
Vest4		0.12
MPC		0.19
ClinPred		0.033	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.56
Mutation Taster		=60/40	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: -2

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

Other links and lift over

dbSNP: rs10134537; hg19: chr14-24760764; COSMIC: COSV55384222; COSMIC: COSV55384222;