19-55146635-GC-GCC

Variant names:

• chr19-55146635-G-GC
• rs772892687
• NM_003283.6:c.73+45dupG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.353
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• nemaline myopathy 5

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• nemaline myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen
• nemaline myopathy 5C, autosomal dominant

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -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. GnomAdExome4 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 GnomAdExome4. There are 1943 alleles in the male GnomAdExome4 subpopulation. Median coverage is 15. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 20 AR,AD gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 384 AN: 140936 Hom.: 1 Cov.: 31

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

GnomAD2 exomes AF: 0.00288 AC: 101 AN: 35046 AF XY: 0.00271

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 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.: 20 Cov.: 15 AF XY: 0.0112 AC XY: 1943 AN XY: 174202

African (AFR) AF: 0.00424 AC: 27 AN: 6370

American (AMR) AF: 0.00195 AC: 20 AN: 10274

Ashkenazi Jewish (ASJ) AF: 0.000621 AC: 4 AN: 6440

East Asian (EAS) AF: 0.00172 AC: 11 AN: 6408

South Asian (SAS) AF: 0.000338 AC: 13 AN: 38442

European-Finnish (FIN) AF: 0.00216 AC: 37 AN: 17118

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 976

European-Non Finnish (NFE) AF: 0.0160 AC: 3811 AN: 237660

Other (OTH) AF: 0.0112 AC: 167 AN: 14952

GnomAD4 genome AF: 0.00272 AC: 384 AN: 141064 Hom.: 1 Cov.: 31 AF XY: 0.00255 AC XY: 175 AN XY: 68642

African (AFR) AF: 0.000990 AC: 39 AN: 39382

American (AMR) AF: 0.000628 AC: 9 AN: 14334

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3280

East Asian (EAS) AF: 0.000236 AC: 1 AN: 4234

South Asian (SAS) AF: 0.000521 AC: 2 AN: 3842

European-Finnish (FIN) AF: 0.000665 AC: 6 AN: 9024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00501 AC: 320 AN: 63844

Other (OTH) AF: 0.00354 AC: 7 AN: 1980

Alfa AF: 0.00125 Hom.: 1

Bravo AF: 0.00258

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs772892687; hg19: chr19-55658003;