15-40471224-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_130468.4(CHST14):c.11G>C(p.Arg4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,342,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. R4C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000034 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 0 hom. )

Consequence

CHST14
NM_130468.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.58

Variant links:

Genes affected

CHST14 (HGNC:24464): (carbohydrate sulfotransferase 14) This gene encodes a member of the HNK-1 family of sulfotransferases. The encoded protein transfers sulfate to the C-4 hydroxyl of N-acetylgalactosamine residues in dermatan sulfate. Mutations in this gene have been associated with adducted thumb-clubfoot syndrome.[provided by RefSeq, Mar 2010]

CHST14 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.33748484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHST14	NM_130468.4 linkuse as main transcript	c.11G>C	p.Arg4Pro	missense_variant	1/1	ENST00000306243.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHST14	ENST00000306243.7 linkuse as main transcript	c.11G>C	p.Arg4Pro	missense_variant	1/1		NM_130468.4	P1
CHST14	ENST00000559991.1 linkuse as main transcript	c.11G>C	p.Arg4Pro	missense_variant	1/2	5

Frequencies

GnomAD3 genomes

AF:

0.0000337

AC:

AN:

148264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000747

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000374

AC:

AN:

26704

Hom.:

AF XY:

0.0000631

AC XY:

AN XY:

15842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000919

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000180

AC:

215

AN:

1193830

Hom.:

Cov.:

AF XY:

0.000158

AC XY:

AN XY:

583216

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000213

Gnomad4 OTH exome

AF:

0.000105

GnomAD4 genome

AF:

0.0000337

AC:

AN:

148264

Hom.:

Cov.:

AF XY:

0.0000554

AC XY:

AN XY:

72254

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000747

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, musculocontractural type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 10, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 4 of the CHST14 protein (p.Arg4Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CHST14-related conditions. ClinVar contains an entry for this variant (Variation ID: 1004396). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2023

The c.11G>C (p.R4P) alteration is located in exon 1 (coding exon 1) of the CHST14 gene. This alteration results from a G to C substitution at nucleotide position 11, causing the arginine (R) at amino acid position 4 to be replaced by a proline (P). 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

0.078

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

Cadd

Pathogenic

Dann

Uncertain

0.99

DEOGEN2

Benign

0.014

T;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.56

T;T

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.34

T;T

MetaSVM

Benign

-0.29

MutationAssessor

Benign

0.34

N;.

MutationTaster

Benign

0.94

D;D

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-0.31

N;N

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

D;D

Sift4G

Benign

0.13

T;T

Polyphen

1.0

D;.

Vest4

0.25

MutPred

0.18

Gain of glycosylation at R4 (P = 0.0064);Gain of glycosylation at R4 (P = 0.0064);

MVP

0.71

MPC

2.4

ClinPred

0.35

GERP RS

3.1

Varity_R

0.30

gMVP

0.71

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over