rs397514706

Positions:

• chr15-40472034-G-C
• chr15-40472034-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_130468.4(CHST14):​c.821G>C​(p.Arg274Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,888 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: CHST14 NM_130468.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.57

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40472034-G-C is Pathogenic according to our data. Variant chr15-40472034-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 50992.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.14018291). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHST14	NM_130468.4	c.821G>C	p.Arg274Pro	missense_variant	1/1	ENST00000306243.7	NP_569735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHST14	ENST00000306243.7	c.821G>C	p.Arg274Pro	missense_variant	1/1		NM_130468.4	ENSP00000307297	P1
CHST14	ENST00000559991.1	c.746G>C	p.Arg249Pro	missense_variant	2/2	5		ENSP00000453882

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461888 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome, musculocontractural type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.21
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.90	D;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.80	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	1.3	N;N
REVEL	Uncertain	0.35
Sift	Benign	0.073	T;T
Sift4G	Benign	0.17	T;T
Polyphen		0.0060	B;.
Vest4		0.22
MutPred		0.52		Gain of loop (P = 0.0097);.;
MVP		0.98
MPC		1.3
ClinPred		0.15	T
GERP RS		3.0
Varity_R		0.61
gMVP		0.81

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: rs397514706; hg19: chr15-40764233; COSMIC: COSV60378528; COSMIC: COSV60378528;