chr14-23990232-T-C

Variant names:

• chr14-23990232-T-C
• rs529238562
• NM_198083.4:c.179T>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_198083.4(DHRS4L2):​c.179T>C​(p.Val60Ala) variant causes a missense change. The variant allele was found at a frequency of 0.000561 in 1,612,504 control chromosomes in the GnomAD database, including 18 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00037 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00058 (16 hom.)
• Consequence: DHRS4L2 NM_198083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.88
• Publications: 2 publications found

Genes affected

DHRS4L2 (HGNC:19731): (dehydrogenase/reductase 4 like 2) This gene encodes a member of the short chain dehydrogenase reductase family. The encoded protein may be an NADPH dependent retinol oxidoreductase. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2010]

DHRS4L1 (HGNC:):

DHRS4-AS1 (HGNC:23175): (DHRS4 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198083.4. 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
	DHRS4L2	NM_198083.4	MANE Select	c.179T>C	p.Val60Ala	missense	Exon 2 of 8	NP_932349.2	Q6PKH6-1
	DHRS4L2	NM_001193635.1		c.95T>C	p.Val32Ala	missense	Exon 4 of 9	NP_001180564.1	D5KJA1
	DHRS4L2	NM_001193636.1		c.-125T>C		5_prime_UTR	Exon 2 of 8	NP_001180565.1	A0A087WSZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DHRS4L2	ENST00000335125.11	TSL:1 MANE Select	c.179T>C	p.Val60Ala	missense	Exon 2 of 8	ENSP00000334801.6	Q6PKH6-1
	DHRS4L2	ENST00000559411.5	TSL:5	c.179T>C	p.Val60Ala	missense	Exon 2 of 7	ENSP00000453889.1	Q6PKH6-2
	DHRS4L2	ENST00000870060.1		c.179T>C	p.Val60Ala	missense	Exon 2 of 8	ENSP00000540119.1

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 151898 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000319 AC: 80 AN: 250786 AF XY: 0.000391

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000529

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000581 AC: 848 AN: 1460490 Hom.: 16 Cov.: 31 AF XY: 0.000578 AC XY: 420 AN XY: 726522

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000209 AC: 7 AN: 33462

American (AMR) AF: 0.000447 AC: 20 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86126

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53180

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5762

European-Non Finnish (NFE) AF: 0.000682 AC: 758 AN: 1111092

Other (OTH) AF: 0.000679 AC: 41 AN: 60350

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152014 Hom.: 2 Cov.: 32 AF XY: 0.000310 AC XY: 23 AN XY: 74292

African (AFR) AF: 0.0000241 AC: 1 AN: 41516

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10496

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000662 AC: 45 AN: 67946

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000513 Hom.: 0

ExAC AF: 0.000255 AC: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	0.0025	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.074	T
Eigen	Benign	0.070
Eigen_PC	Benign	0.023
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.42	D
PhyloP100		6.9
PROVEAN	Uncertain	-3.8	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.070	T
Polyphen		0.36	B
Vest4		0.65
MVP		0.85
MPC		0.24
ClinPred		0.18	T
GERP RS		3.4
PromoterAI		-0.067	Neutral
gMVP		0.68
Mutation Taster		=286/14	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: rs529238562; hg19: chr14-24459441;