rs890868

Variant names:

• chr19-55132957-C-A
• rs890868
• NM_003283.6:c.795G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-55132957-C-A
• chr19-55132957-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003283.6(TNNT1):​c.795G>T​(p.Arg265Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00478 in 1,601,424 control chromosomes in the GnomAD database, including 241 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0072 (18 hom., cov: 31)
  • Exomes 𝑓: 0.0045 (223 hom.)
• Consequence: TNNT1 NM_003283.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 0.333
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-55132957-C-A is Benign according to our data. Variant chr19-55132957-C-A is described in ClinVar as Benign. ClinVar VariationId is 31857.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.333 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0625 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003283.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	NM_003283.6	MANE Select	c.795G>T	p.Arg265Arg	synonymous	Exon 14 of 14	NP_003274.3
	TNNT1	NM_001126132.3		c.747G>T	p.Arg249Arg	synonymous	Exon 14 of 14	NP_001119604.1
	TNNT1	NM_001126133.3		c.714G>T	p.Arg238Arg	synonymous	Exon 13 of 13	NP_001119605.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNNT1	ENST00000588981.6	TSL:1 MANE Select	c.795G>T	p.Arg265Arg	synonymous	Exon 14 of 14	ENSP00000467176.1
	TNNT1	ENST00000291901.12	TSL:1	c.747G>T	p.Arg249Arg	synonymous	Exon 14 of 14	ENSP00000291901.8
	TNNT1	ENST00000356783.9	TSL:1	c.714G>T	p.Arg238Arg	synonymous	Exon 13 of 13	ENSP00000349233.4

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1092 AN: 152166 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0689

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.00191

GnomAD4 exome AF: 0.00453 AC: 6571 AN: 1449138 Hom.: 223 Cov.: 31 AF XY: 0.00423 AC XY: 3045 AN XY: 719514

African (AFR) AF: 0.000240 AC: 8 AN: 33396

American (AMR) AF: 0.0440 AC: 1865 AN: 42380

Ashkenazi Jewish (ASJ) AF: 0.0000777 AC: 2 AN: 25740

East Asian (EAS) AF: 0.0888 AC: 3496 AN: 39348

South Asian (SAS) AF: 0.00160 AC: 134 AN: 83552

European-Finnish (FIN) AF: 0.0143 AC: 741 AN: 51672

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5754

European-Non Finnish (NFE) AF: 0.000116 AC: 129 AN: 1107326

Other (OTH) AF: 0.00325 AC: 195 AN: 59970

GnomAD4 genome AF: 0.00716 AC: 1090 AN: 152286 Hom.: 18 Cov.: 31 AF XY: 0.00902 AC XY: 672 AN XY: 74462

African (AFR) AF: 0.000192 AC: 8 AN: 41560

American (AMR) AF: 0.0326 AC: 499 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0684 AC: 354 AN: 5174

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4824

European-Finnish (FIN) AF: 0.0174 AC: 185 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000426 AC: 29 AN: 68036

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00317 Hom.: 8

Bravo AF: 0.00869

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Nemaline myopathy 5 (1)
-	-	1	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
PhyloP100		0.33

Splicing

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

Other links and lift over

dbSNP: rs890868; hg19: chr19-55644325;