17-39665360-A-T

Variant names:

• chr17-39665360-A-T
• rs1567864804
• NM_003673.4:c.1A>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_003673.4(TCAP):​c.1A>T​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: TCAP NM_003673.4 initiator_codon
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.16

Genes affected

TCAP (HGNC:11610): (titin-cap) Sarcomere assembly is regulated by the muscle protein titin. Titin is a giant elastic protein with kinase activity that extends half the length of a sarcomere. It serves as a scaffold to which myofibrils and other muscle related proteins are attached. This gene encodes a protein found in striated and cardiac muscle that binds to the titin Z1-Z2 domains and is a substrate of titin kinase, interactions thought to be critical to sarcomere assembly. Mutations in this gene are associated with limb-girdle muscular dystrophy type 2G. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 9 pathogenic variants. Next in-frame start position is after 68 codons. Genomic position: 39665807. Lost 0.401 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-39665360-A-T is Pathogenic according to our data. Variant chr17-39665360-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3752172.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCAP	NM_003673.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 2	ENST00000309889.3	NP_003664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCAP	ENST00000309889.3	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 2	1	NM_003673.4	ENSP00000312624.2
TCAP	ENST00000578283.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 1 of 3	5		ENSP00000462787.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461242 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726914

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: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary familial hypertrophic cardiomyopathy;C4225408:Hypertrophic cardiomyopathy 25 Pathogenic:1

Apr 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the TCAP mRNA. The next in-frame methionine is located at codon 68. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with autosomal recessive limb-girdle muscular dystrophy (PMID: 34982307). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.16	T;.
Eigen	Benign	-0.13
Eigen_PC	Benign	0.021
FATHMM_MKL	Benign	0.69	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.69	D;D
MetaSVM	Benign	-0.45	T
PROVEAN	Benign	-0.66	N;.
REVEL	Uncertain	0.51
Sift	Benign	0.45	T;.
Sift4G	Benign	0.70	T;T
Polyphen		0.15	B;.
Vest4		0.52
MutPred		0.57		Gain of sheet (P = 0.1945);Gain of sheet (P = 0.1945);
MVP		0.91
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.73
gMVP		0.077

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: 13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1567864804; hg19: chr17-37821613;