17-15438174-G-A

Variant names:

• chr17-15438174-G-A
• rs781118198
• NM_001204477.2:c.58C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001204477.2(CDRT4):​c.58C>T​(p.Arg20Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,613,776 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (1 hom.)
• Consequence: CDRT4 NM_001204477.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.123

Genes affected

CDRT4 (HGNC:14383): (CMT1A duplicated region transcript 4)

TVP23C-CDRT4 (HGNC:42961): (TVP23C-CDRT4 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring TVP23C (trans-golgi network vesicle protein 23 homolog) and CDRT4 (CMT1A duplicated region transcript 4) genes on chromosome 17. Alternative splicing results in multiple transcript variants, one of which encodes a protein that shares sequence identity with the upstream gene product, but its C-terminus is distinct due to frameshifts relative to the downstream gene. [provided by RefSeq, Apr 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.079966635).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDRT4	NM_001204477.2	c.58C>T	p.Arg20Trp	missense_variant	Exon 4 of 4	ENST00000619038.5	NP_001191406.1
TVP23C-CDRT4	NM_001204478.2	c.*72C>T		3_prime_UTR_variant	Exon 7 of 7		NP_001191407.1
TVP23C-CDRT4	NR_037924.2	n.457C>T		non_coding_transcript_exon_variant	Exon 6 of 6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDRT4	ENST00000619038.5	c.58C>T	p.Arg20Trp	missense_variant	Exon 4 of 4	1	NM_001204477.2	ENSP00000482523.1
TVP23C-CDRT4	ENST00000522212	c.*72C>T		3_prime_UTR_variant	Exon 7 of 7	2		ENSP00000429865.1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000519 AC: 13 AN: 250680 Hom.: 1 AF XY: 0.0000591 AC XY: 8 AN XY: 135470

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461636 Hom.: 1 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727116

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74314

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 17, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.58C>T (p.R20W) alteration is located in exon 4 (coding exon 2) of the CDRT4 gene. This alteration results from a C to T substitution at nucleotide position 58, causing the arginine (R) at amino acid position 20 to be replaced by a tryptophan (W). 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	Benign	0.082
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.46
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.43	T;T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.080	T;T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.24	T
PROVEAN	Pathogenic	-7.3	.;D
REVEL	Benign	0.14
Sift4G	Benign	0.13	T;.
Vest4		0.088
MVP		0.030
ClinPred		0.062	T
GERP RS		-0.62
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.026

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs781118198; hg19: chr17-15341491;