15-40471245-C-T

Variant summary

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

The NM_130468.4(CHST14):c.32C>T(p.Ala11Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000256 in 1,447,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CHST14 NM_130468.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.158

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]

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=0.09394148).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHST14	NM_130468.4	c.32C>T	p.Ala11Val	missense_variant	1/1	ENST00000306243.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHST14	ENST00000306243.7	c.32C>T	p.Ala11Val	missense_variant	1/1		NM_130468.4	P1
CHST14	ENST00000559991.1	c.32C>T	p.Ala11Val	missense_variant	1/2	5

Frequencies

GnomAD3 genomes AF: 0.0000987 AC: 15 AN: 151934 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000170 AC: 1 AN: 58792 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 34518

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000100

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000170 AC: 22 AN: 1295840 Hom.: 0 Cov.: 32 AF XY: 0.0000141 AC XY: 9 AN XY: 637374

Gnomad4 AFR exome AF: 0.0000792

Gnomad4 AMR exome AF: 0.0000497

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: 0.0000182

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000987 AC: 15 AN: 152042 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74344

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.0000718

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, musculocontractural type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 09, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 1045341). This variant has not been reported in the literature in individuals affected with CHST14-related conditions. 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 sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 11 of the CHST14 protein (p.Ala11Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.26	N
LIST_S2	Benign	0.54	T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.094	T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.34	N;.
MutationTaster	Benign	0.79	N;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.36	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.29	T;T
Polyphen		0.078	B;.
Vest4		0.099
MutPred		0.11		Gain of catalytic residue at A11 (P = 0.1584);Gain of catalytic residue at A11 (P = 0.1584);
MVP		0.29
MPC		0.90
ClinPred		0.068	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.13
gMVP		0.26

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: rs1030815676; hg19: chr15-40763444; COSMIC: COSV105111340; COSMIC: COSV105111340;