9-35683244-G-GT

Position:

• chr9-35683244-G-GT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003289.4(TPM2):​c.773-4_773-3insA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00198 in 1,450,610 control chromosomes in the GnomAD database, including 50 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (23 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (27 hom.)
• Consequence: TPM2 NM_003289.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.24

Genes affected

TPM2 (HGNC:12011): (tropomyosin 2) This gene encodes beta-tropomyosin, a member of the actin filament binding protein family, and mainly expressed in slow, type 1 muscle fibers. Mutations in this gene can alter the expression of other sarcomeric tropomyosin proteins, and cause cap disease, nemaline myopathy and distal arthrogryposis syndromes. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2009]

TPM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 9-35683244-G-GT is Benign according to our data. Variant chr9-35683244-G-GT is described in ClinVar as [Likely_benign]. Clinvar id is 366769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0196 (1292/65916) while in subpopulation AFR AF= 0.0524 (1200/22910). AF 95% confidence interval is 0.0499. There are 23 homozygotes in gnomad4. There are 621 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1292 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPM2	NM_003289.4	c.773-4_773-3insA		splice_region_variant, intron_variant		ENST00000645482.3	NP_003280.2
TPM2	NM_001301226.2	c.772+1001_772+1002insA		intron_variant			NP_001288155.1
TPM2	NM_001301227.2	c.773-4_773-3insA		splice_region_variant, intron_variant			NP_001288156.1
TPM2	NM_213674.1	c.772+1001_772+1002insA		intron_variant			NP_998839.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPM2	ENST00000645482.3	c.773-4_773-3insA		splice_region_variant, intron_variant			NM_003289.4	ENSP00000496494.2

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 1286 AN: 65820 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0522

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00971

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0288

Gnomad NFE AF: 0.000504

Gnomad OTH AF: 0.0194

GnomAD3 exomes AF: 0.00443 AC: 333 AN: 75160 Hom.: 3 AF XY: 0.00351 AC XY: 140 AN XY: 39894

Gnomad AFR exome AF: 0.0500

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000698

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000448

Gnomad OTH exome AF: 0.00543

GnomAD4 exome AF: 0.00114 AC: 1581 AN: 1384694 Hom.: 27 Cov.: 34 AF XY: 0.00104 AC XY: 711 AN XY: 683636

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.00216

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000106

Gnomad4 OTH exome AF: 0.00357

GnomAD4 genome AF: 0.0196 AC: 1292 AN: 65916 Hom.: 23 Cov.: 33 AF XY: 0.0189 AC XY: 621 AN XY: 32818

Gnomad4 AFR AF: 0.0524

Gnomad4 AMR AF: 0.00967

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000504

Gnomad4 OTH AF: 0.0190

Alfa AF: 0.00445 Hom.: 0

Bravo AF: 0.00991

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2016	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. -

Nemaline Myopathy, Dominant Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arthrogryposis, distal, type 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

Arthrogryposis multiplex congenita Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1554658501; hg19: chr9-35683241;