15-40471418-A-T

Variant names:

• chr15-40471418-A-T
• rs267606730
• NM_130468.4:c.205A>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_130468.4(CHST14):​c.205A>T​(p.Lys69*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHST14 NM_130468.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.15
• Publications: 3 publications found

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

ENSG00000302612 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 26 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 15-40471418-A-T is Pathogenic according to our data. Variant chr15-40471418-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2341.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130468.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST14	NM_130468.4	MANE Select	c.205A>T	p.Lys69*	stop_gained	Exon 1 of 1	NP_569735.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHST14	ENST00000306243.7	TSL:6 MANE Select	c.205A>T	p.Lys69*	stop_gained	Exon 1 of 1	ENSP00000307297.6
	CHST14	ENST00000559991.1	TSL:5	c.205A>T	p.Lys69*	stop_gained	Exon 1 of 2	ENSP00000453882.1
	ENSG00000302612	ENST00000788112.1		n.151+237T>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1407194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 696498

African (AFR) AF: 0.00 AC: 0 AN: 32414

American (AMR) AF: 0.00 AC: 0 AN: 37550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.00 AC: 0 AN: 36842

South Asian (SAS) AF: 0.00 AC: 0 AN: 81096

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088770

Other (OTH) AF: 0.00 AC: 0 AN: 58590

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Ehlers-Danlos syndrome, musculocontractural type 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.89	D
PhyloP100		3.1
Vest4		0.094
GERP RS		4.4
PromoterAI		-0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=9/191	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs267606730; hg19: chr15-40763617;