chr2-18555567-T-A

Variant names:

• chr2-18555567-T-A
• rs138843648
• NM_020905.4:c.635A>T

Variant summary

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

The NM_020905.4(RDH14):​c.635A>T​(p.Asn212Ile) variant causes a missense change. 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: RDH14 NM_020905.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.25

Genes affected

RDH14 (HGNC:19979): (retinol dehydrogenase 14) Enables NADP-retinol dehydrogenase activity. Involved in osteoblast differentiation. Located in cytosol; endoplasmic reticulum; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NT5C1B-RDH14 (HGNC:38831): (NT5C1B-RDH14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NT5C1B (5'-nucleotidase, cytosolic IB) and RDH14 (retinol dehydrogenase 14) genes on chromosome 2. Alternative splicing results in multiple transcript variants, one of which encodes a fusion protein that shares sequence identity with the products of each individual gene. [provided by RefSeq, Nov 2010]

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 rank	MANE	Protein	UniProt
RDH14	NM_020905.4	c.635A>T	p.Asn212Ile	missense_variant	Exon 2 of 2	ENST00000381249.4	NP_065956.1
NT5C1B-RDH14	NM_001199103.2	c.1577A>T	p.Asn526Ile	missense_variant	Exon 9 of 9		NP_001186032.1
NT5C1B-RDH14	NM_001199104.2	c.*217A>T		3_prime_UTR_variant	Exon 11 of 11		NP_001186033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDH14	ENST00000381249.4	c.635A>T	p.Asn212Ile	missense_variant	Exon 2 of 2	1	NM_020905.4	ENSP00000370648.3
NT5C1B-RDH14	ENST00000532967	c.*217A>T		3_prime_UTR_variant	Exon 11 of 11	2		ENSP00000433415.1
NT5C1B-RDH14	ENST00000444297.2	c.1577A>T	p.Asn526Ile	missense_variant	Exon 9 of 9	2		ENSP00000412639.2
RDH14	ENST00000468071.1	n.292A>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 05, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.635A>T (p.N212I) alteration is located in exon 2 (coding exon 2) of the RDH14 gene. This alteration results from a A to T substitution at nucleotide position 635, causing the asparagine (N) at amino acid position 212 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
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	D;.
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.82	T;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	2.0	M;.
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.54	P;D
Vest4		0.61
MVP		0.99
MPC		0.16
ClinPred		0.96	D
GERP RS		3.3
Varity_R		0.41
gMVP		0.89

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: rs138843648; hg19: chr2-18736833;