rs75137889

Variant names:

• chr19-7932690-C-T
• rs75137889
• NM_006351.4:c.924G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006351.4(TIMM44):​c.924G>A​(p.Pro308Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,614,134 control chromosomes in the GnomAD database, including 165 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (8 hom., cov: 33)
  • Exomes 𝑓: 0.013 (157 hom.)
• Consequence: TIMM44 NM_006351.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.69
• Publications: 6 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 19-7932690-C-T is Benign according to our data. Variant chr19-7932690-C-T is described in ClinVar as Benign. ClinVar VariationId is 137646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.69 with no splicing effect.
• BS2: High AC in GnomAd4 at 1392 AD gene.

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.924G>A	p.Pro308Pro	synonymous	Exon 9 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.924G>A	p.Pro308Pro	synonymous	Exon 9 of 13	ENSP00000270538.2	O43615
	TIMM44	ENST00000595876.5	TSL:1	n.*612G>A		non_coding_transcript_exon	Exon 9 of 11	ENSP00000471596.1	M0R124
	TIMM44	ENST00000595876.5	TSL:1	n.*612G>A		3_prime_UTR	Exon 9 of 11	ENSP00000471596.1	M0R124

Frequencies

GnomAD3 genomes AF: 0.00914 AC: 1391 AN: 152194 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0241

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0135

Gnomad OTH AF: 0.00573

GnomAD2 exomes AF: 0.0110 AC: 2755 AN: 251356 AF XY: 0.0111

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0283

Gnomad NFE exome AF: 0.0142

Gnomad OTH exome AF: 0.0122

GnomAD4 exome AF: 0.0133 AC: 19380 AN: 1461822 Hom.: 157 Cov.: 31 AF XY: 0.0130 AC XY: 9447 AN XY: 727216

African (AFR) AF: 0.00194 AC: 65 AN: 33480

American (AMR) AF: 0.00286 AC: 128 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00325 AC: 85 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00924 AC: 797 AN: 86258

European-Finnish (FIN) AF: 0.0286 AC: 1529 AN: 53370

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5764

European-Non Finnish (NFE) AF: 0.0144 AC: 16048 AN: 1111998

Other (OTH) AF: 0.0113 AC: 682 AN: 60396

GnomAD4 genome AF: 0.00914 AC: 1392 AN: 152312 Hom.: 8 Cov.: 33 AF XY: 0.00933 AC XY: 695 AN XY: 74470

African (AFR) AF: 0.00241 AC: 100 AN: 41568

American (AMR) AF: 0.00216 AC: 33 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00890 AC: 43 AN: 4830

European-Finnish (FIN) AF: 0.0241 AC: 256 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0135 AC: 920 AN: 68010

Other (OTH) AF: 0.00567 AC: 12 AN: 2116

Alfa AF: 0.0112 Hom.: 7

Bravo AF: 0.00703

Asia WGS AF: 0.00404 AC: 14 AN: 3478

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	-0.69
CADD	Benign	0.69
DANN	Benign	0.66
PhyloP100		-2.7
PromoterAI		-0.0063	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs75137889; hg19: chr19-7997575;