19-55141344-G-C

Variant names:

• chr19-55141344-G-C
• rs73060953
• NM_003283.6:c.193-42C>G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003283.6(TNNT1):​c.193-42C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.039 in 1,498,868 control chromosomes in the GnomAD database, including 1,242 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (98 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1144 hom.)
• Consequence: TNNT1 NM_003283.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0950

Genes affected

TNNT1 (HGNC:11948): (troponin T1, slow skeletal type) This gene encodes a protein that is a subunit of troponin, which is a regulatory complex located on the thin filament of the sarcomere. This complex regulates striated muscle contraction in response to fluctuations in intracellular calcium concentration. This complex is composed of three subunits: troponin C, which binds calcium, troponin T, which binds tropomyosin, and troponin I, which is an inhibitory subunit. This protein is the slow skeletal troponin T subunit. Mutations in this gene cause nemaline myopathy type 5, also known as Amish nemaline myopathy, a neuromuscular disorder characterized by muscle weakness and rod-shaped, or nemaline, inclusions in skeletal muscle fibers which affects infants, resulting in death due to respiratory insufficiency, usually in the second year. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 19-55141344-G-C is Benign according to our data. Variant chr19-55141344-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 259030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0337 (5138/152288) while in subpopulation NFE AF= 0.0419 (2850/68012). AF 95% confidence interval is 0.0406. There are 98 homozygotes in gnomad4. There are 2537 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 98 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT1	NM_003283.6	c.193-42C>G		intron_variant	Intron 7 of 13	ENST00000588981.6	NP_003274.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6	c.193-42C>G		intron_variant	Intron 7 of 13	1	NM_003283.6	ENSP00000467176.1

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5140 AN: 152170 Hom.: 98 Cov.: 32

Gnomad AFR AF: 0.0190

Gnomad AMI AF: 0.0877

Gnomad AMR AF: 0.0358

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.0177

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0419

Gnomad OTH AF: 0.0415

GnomAD3 exomes AF: 0.0332 AC: 8310 AN: 250398 Hom.: 174 AF XY: 0.0335 AC XY: 4536 AN XY: 135480

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0218

Gnomad ASJ exome AF: 0.0414

Gnomad EAS exome AF: 0.0168

Gnomad SAS exome AF: 0.0146

Gnomad FIN exome AF: 0.0402

Gnomad NFE exome AF: 0.0441

Gnomad OTH exome AF: 0.0401

GnomAD4 exome AF: 0.0396 AC: 53320 AN: 1346580 Hom.: 1144 Cov.: 21 AF XY: 0.0390 AC XY: 26400 AN XY: 676308

Gnomad4 AFR exome AF: 0.0207

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.0399

Gnomad4 EAS exome AF: 0.0229

Gnomad4 SAS exome AF: 0.0160

Gnomad4 FIN exome AF: 0.0399

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0386

GnomAD4 genome AF: 0.0337 AC: 5138 AN: 152288 Hom.: 98 Cov.: 32 AF XY: 0.0341 AC XY: 2537 AN XY: 74476

Gnomad4 AFR AF: 0.0190

Gnomad4 AMR AF: 0.0357

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.0180

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0433

Gnomad4 NFE AF: 0.0419

Gnomad4 OTH AF: 0.0411

Alfa AF: 0.0385 Hom.: 28

Bravo AF: 0.0326

Asia WGS AF: 0.0120 AC: 44 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.030
DANN	Benign	0.46

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: rs73060953; hg19: chr19-55652712;