Genetic Variant NM_130468.4:c.23C>T (chr15-40471236-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_130468.4(CHST14):c.23C>T(p.Pro8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CHST14
NM_130468.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.27

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, musculocontractural type 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
Ehlers-Danlos syndrome, musculocontractural type
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHST14 links:

ENSG00000302612 (HGNC:):

ENSG00000302612 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.22300196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHST14	NM_130468.4 link	c.23C>T	p.Pro8Leu	missense_variant	Exon 1 of 1	ENST00000306243.7	NP_569735.1	Q8NCH0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHST14	ENST00000306243.7 link	c.23C>T	p.Pro8Leu	missense_variant	Exon 1 of 1	6	NM_130468.4	ENSP00000307297.6	Q8NCH0
CHST14	ENST00000559991.1 link	c.23C>T	p.Pro8Leu	missense_variant	Exon 1 of 2	5		ENSP00000453882.1	H0YN65
ENSG00000302612	ENST00000788112.1 link	n.151+419G>A		intron_variant	Intron 1 of 4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1280082

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

628580

African (AFR)

AF:

0.00

AC:

AN:

24784

American (AMR)

AF:

0.00

AC:

AN:

17716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19536

East Asian (EAS)

AF:

0.00

AC:

AN:

29788

South Asian (SAS)

AF:

0.00

AC:

AN:

64436

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32108

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3722

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1035218

Other (OTH)

AF:

0.00

AC:

AN:

52774

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Uncertain:1

Oct 21, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.P8L variant (also known as c.23C>T), located in coding exon 1 of the CHST14 gene, results from a C to T substitution at nucleotide position 23. The proline at codon 8 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

0.0049

BayesDel_noAF

Benign

-0.23

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.031

T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.50

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.65

T;T

M_CAP

Pathogenic

0.90

MetaRNN

Benign

0.22

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.34

N;.

PhyloP100

1.3

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.91

N;N

REVEL

Benign

0.17

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.022

D;D

Polyphen

0.056

B;.

Vest4

0.35

MutPred

0.19

Loss of loop (P = 0.0075);Loss of loop (P = 0.0075);

MVP

0.23

MPC

2.1

ClinPred

0.48

GERP RS

0.98

PromoterAI

-0.0072

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.15

gMVP

0.31

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over