chr14-23995092-T-A

Position:

• chr14-23995092-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_198083.4(DHRS4L2):​c.367T>A​(p.Phe123Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DHRS4L2 NM_198083.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.51

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DHRS4L2	NM_198083.4	c.367T>A	p.Phe123Ile	missense_variant	3/8	ENST00000335125.11	NP_932349.2
DHRS4L2	NM_001193636.1	c.64T>A	p.Phe22Ile	missense_variant	3/8		NP_001180565.1
DHRS4L2	NM_001193637.1	c.64T>A	p.Phe22Ile	missense_variant	3/6		NP_001180566.1
DHRS4L2	NM_001193635.1	c.222+4733T>A		intron_variant			NP_001180564.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DHRS4L2	ENST00000335125.11	c.367T>A	p.Phe123Ile	missense_variant	3/8	1	NM_198083.4	ENSP00000334801.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2024

The c.367T>A (p.F123I) alteration is located in exon 3 (coding exon 3) of the DHRS4L2 gene. This alteration results from a T to A substitution at nucleotide position 367, causing the phenylalanine (F) at amino acid position 123 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	15
DANN	Benign	0.97
DEOGEN2	Benign	0.036	T;T;T;T;.
Eigen	Benign	-0.11
Eigen_PC	Benign	0.0093
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.89	D;D;D;D;.
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.64	D;D;D;D;D
MetaSVM	Benign	-0.53	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Uncertain	0.58
Sift	Benign	0.27	T;.;T;T;T
Sift4G	Benign	0.084	T;T;T;T;T
Vest4		0.60
MVP		0.86
MPC		0.046
ClinPred		0.71	D
GERP RS		4.6
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs2034352730; hg19: chr14-24464301;