Genetic Variant NM_003283.6:c.73+45dupG (chr19-55146635-G-GC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_003283.6(TNNT1):c.73+45dupG variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00933 in 479,704 control chromosomes in the GnomAD database, including 21 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 1 hom., cov: 31)

Exomes 𝑓: 0.012 ( 20 hom. )

Consequence

TNNT1
NM_003283.6 intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.353

Variant links:

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]

TNNT1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant 19-55146635-G-GC is Benign according to our data. Variant chr19-55146635-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 259032.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0121 (4090/338640) while in subpopulation NFE AF= 0.016 (3811/237660). AF 95% confidence interval is 0.0156. There are 20 homozygotes in gnomad4_exome. There are 1943 alleles in male gnomad4_exome subpopulation. Median coverage is 15. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 20 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNNT1	NM_003283.6 link	c.73+45dupG		intron_variant	Intron 4 of 13	ENST00000588981.6	NP_003274.3	P13805-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNNT1	ENST00000588981.6 link	c.73+45_73+46insG		intron_variant	Intron 4 of 13	1	NM_003283.6	ENSP00000467176.1		P13805-1

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

384

AN:

140936

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000993

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000629

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000236

Gnomad SAS

AF:

0.000522

Gnomad FIN

AF:

0.000665

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00501

Gnomad OTH

AF:

0.00358

GnomAD3 exomes

AF:

0.00288

AC:

101

AN:

35046

Hom.:

AF XY:

0.00271

AC XY:

AN XY:

18450

show subpopulations

Gnomad AFR exome

AF:

0.00200

Gnomad AMR exome

AF:

0.00149

Gnomad ASJ exome

AF:

0.000919

Gnomad EAS exome

AF:

0.000273

Gnomad SAS exome

AF:

0.000412

Gnomad FIN exome

AF:

0.000617

Gnomad NFE exome

AF:

0.00747

Gnomad OTH exome

AF:

0.00190

GnomAD4 exome

AF:

0.0121

AC:

4090

AN:

338640

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

1943

AN XY:

174202

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.00195

Gnomad4 ASJ exome

AF:

0.000621

Gnomad4 EAS exome

AF:

0.00172

Gnomad4 SAS exome

AF:

0.000338

Gnomad4 FIN exome

AF:

0.00216

Gnomad4 NFE exome

AF:

0.0160

Gnomad4 OTH exome

AF:

0.0112

GnomAD4 genome

AF:

0.00272

AC:

384

AN:

141064

Hom.:

Cov.:

AF XY:

0.00255

AC XY:

175

AN XY:

68642

show subpopulations

Gnomad4 AFR

AF:

0.000990

Gnomad4 AMR

AF:

0.000628

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000236

Gnomad4 SAS

AF:

0.000521

Gnomad4 FIN

AF:

0.000665

Gnomad4 NFE

AF:

0.00501

Gnomad4 OTH

AF:

0.00354

Bravo

AF:

0.00258

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over