14-23990204-C-G

Variant names:

• chr14-23990204-C-G
• rs146647822
• NM_198083.4:c.151C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_198083.4(DHRS4L2):​c.151C>G​(p.Arg51Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,460,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R51S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DHRS4L2 NM_198083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44
• Publications: 4 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]

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

DHRS4L1 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.893

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.151C>G	p.Arg51Gly	missense	Exon 2 of 8	NP_932349.2	Q6PKH6-1
	DHRS4L2	NM_001193635.1		c.67C>G	p.Arg23Gly	missense	Exon 4 of 9	NP_001180564.1	D5KJA1
	DHRS4L2	NM_001193636.1		c.-153C>G		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.151C>G	p.Arg51Gly	missense	Exon 2 of 8	ENSP00000334801.6	Q6PKH6-1
	DHRS4L2	ENST00000559411.5	TSL:5	c.151C>G	p.Arg51Gly	missense	Exon 2 of 7	ENSP00000453889.1	Q6PKH6-2
	DHRS4L2	ENST00000870060.1		c.151C>G	p.Arg51Gly	missense	Exon 2 of 8	ENSP00000540119.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000200 AC: 5 AN: 250446 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1460700 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 726592

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000224 AC: 1 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86116

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111364

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

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	Uncertain	0.16	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.084	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.077
FATHMM_MKL	Benign	0.64	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.42	D
PhyloP100		4.4
PROVEAN	Pathogenic	-6.5	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.033	D
Polyphen		0.77	P
Vest4		0.40
MVP		0.85
MPC		0.21
ClinPred		0.86	D
GERP RS		3.4
PromoterAI		0.038	Neutral
gMVP		0.66
Mutation Taster		=289/11	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: rs146647822; hg19: chr14-24459413;