rs11542188

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr19-7927241-G-A
• chr19-7927241-G-C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 12 publications found

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]

TIMM44 Gene-Disease associations (from GenCC):

• thyroid cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006351.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM44	NM_006351.4	MANE Select	c.1305C>T	p.Tyr435Tyr	synonymous	Exon 13 of 13	NP_006342.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMM44	ENST00000270538.8	TSL:1 MANE Select	c.1305C>T	p.Tyr435Tyr	synonymous	Exon 13 of 13	ENSP00000270538.2	O43615
	TIMM44	ENST00000923643.1		c.1293C>T	p.Tyr431Tyr	synonymous	Exon 13 of 13	ENSP00000593702.1
	TIMM44	ENST00000870121.1		c.1275C>T	p.Tyr425Tyr	synonymous	Exon 13 of 13	ENSP00000540180.1

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

GnomAD2 exomes AF: 0.0624 AC: 15441 AN: 247580 AF XY: 0.0619

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 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

African (AFR) AF: 0.103 AC: 3441 AN: 33468

American (AMR) AF: 0.0379 AC: 1693 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0706 AC: 1845 AN: 26130

East Asian (EAS) AF: 0.0486 AC: 1930 AN: 39692

South Asian (SAS) AF: 0.0560 AC: 4827 AN: 86228

European-Finnish (FIN) AF: 0.0704 AC: 3663 AN: 52056

Middle Eastern (MID) AF: 0.0783 AC: 436 AN: 5566

European-Non Finnish (NFE) AF: 0.0716 AC: 79570 AN: 1111908

Other (OTH) AF: 0.0691 AC: 4169 AN: 60344

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

African (AFR) AF: 0.104 AC: 4326 AN: 41552

American (AMR) AF: 0.0584 AC: 893 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0732 AC: 254 AN: 3468

East Asian (EAS) AF: 0.0429 AC: 222 AN: 5170

South Asian (SAS) AF: 0.0471 AC: 227 AN: 4824

European-Finnish (FIN) AF: 0.0663 AC: 703 AN: 10602

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0717 AC: 4873 AN: 68004

Other (OTH) AF: 0.0753 AC: 159 AN: 2112

Alfa AF: 0.0724 Hom.: 247

Bravo AF: 0.0750

Asia WGS AF: 0.0490 AC: 172 AN: 3478

EpiCase AF: 0.0720

EpiControl AF: 0.0710

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	4.9
DANN	Benign	0.95
PhyloP100		0.020
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

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