19-7927241-G-A

Variant names:

• chr19-7927241-G-A
• rs11542188
• NM_006351.4:c.1305C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006351.4(TIMM44):​c.1305C>T​(p.Tyr435Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0703 in 1,612,356 control chromosomes in the GnomAD database, including 4,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.077 (475 hom., cov: 32)
  • Exomes 𝑓: 0.070 (3659 hom.)
• Consequence: TIMM44 NM_006351.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0200

Genes affected

TIMM44 (HGNC:17316): (translocase of inner mitochondrial membrane 44) This gene encodes a peripheral membrane protein associated with the mitochondrial inner membrane translocase, which functions in the import of proteins across the mitochondrial inner membrane and into the mitochondrial matrix. The encoded protein mediates binding of mitochondrial heat shock protein 70 to the translocase of inner mitochondrial membrane 23 (TIM23) complex. Expression of this gene is upregulated in kidney in a mouse model of diabetes. A mutation in this gene is associated with familial oncocytic thyroid carcinoma. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 19-7927241-G-A is Benign according to our data. Variant chr19-7927241-G-A is described in ClinVar as [Benign]. Clinvar id is 137649.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.02 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMM44	NM_006351.4	c.1305C>T	p.Tyr435Tyr	synonymous_variant	Exon 13 of 13	ENST00000270538.8	NP_006342.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMM44	ENST00000270538.8	c.1305C>T	p.Tyr435Tyr	synonymous_variant	Exon 13 of 13	1	NM_006351.4	ENSP00000270538.2

Frequencies

GnomAD3 genomes AF: 0.0771 AC: 11736 AN: 152124 Hom.: 474 Cov.: 32

Gnomad AFR AF: 0.104

Gnomad AMI AF: 0.0833

Gnomad AMR AF: 0.0584

Gnomad ASJ AF: 0.0732

Gnomad EAS AF: 0.0428

Gnomad SAS AF: 0.0472

Gnomad FIN AF: 0.0663

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0717

Gnomad OTH AF: 0.0761

GnomAD3 exomes AF: 0.0624 AC: 15441 AN: 247580 Hom.: 498 AF XY: 0.0619 AC XY: 8323 AN XY: 134474

Gnomad AFR exome AF: 0.104

Gnomad AMR exome AF: 0.0365

Gnomad ASJ exome AF: 0.0706

Gnomad EAS exome AF: 0.0370

Gnomad SAS exome AF: 0.0538

Gnomad FIN exome AF: 0.0718

Gnomad NFE exome AF: 0.0684

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0696 AC: 101574 AN: 1460114 Hom.: 3659 Cov.: 32 AF XY: 0.0690 AC XY: 50130 AN XY: 726438

Gnomad4 AFR exome AF: 0.103

Gnomad4 AMR exome AF: 0.0379

Gnomad4 ASJ exome AF: 0.0706

Gnomad4 EAS exome AF: 0.0486

Gnomad4 SAS exome AF: 0.0560

Gnomad4 FIN exome AF: 0.0704

Gnomad4 NFE exome AF: 0.0716

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.0771 AC: 11745 AN: 152242 Hom.: 475 Cov.: 32 AF XY: 0.0762 AC XY: 5673 AN XY: 74442

Gnomad4 AFR AF: 0.104

Gnomad4 AMR AF: 0.0584

Gnomad4 ASJ AF: 0.0732

Gnomad4 EAS AF: 0.0429

Gnomad4 SAS AF: 0.0471

Gnomad4 FIN AF: 0.0663

Gnomad4 NFE AF: 0.0717

Gnomad4 OTH AF: 0.0753

Alfa AF: 0.0725 Hom.: 188

Bravo AF: 0.0750

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.0720

EpiControl AF: 0.0710

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 23, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jan 09, 2014

GeneDx

Significance: 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.9
DANN	Benign	0.95

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: rs11542188; hg19: chr19-7992126; COSMIC: COSV54491043; COSMIC: COSV54491043;