NM_006351.4:c.1272G>A

Variant names:

• chr19-7927274-C-T
• rs138385134
• NM_006351.4:c.1272G>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.1272G>A​(p.Ala424Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00061 in 1,611,880 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00064 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00061 (1 hom.)
• Consequence: TIMM44 NM_006351.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.33
• Publications: 1 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=-0.51).
• BP6: Variant 19-7927274-C-T is Benign according to our data. Variant chr19-7927274-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 215250.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.33 with no splicing effect.
• BS2: High AC in GnomAd4 at 98 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.1272G>A	p.Ala424Ala	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.1272G>A	p.Ala424Ala	synonymous	Exon 13 of 13	ENSP00000270538.2	O43615
	TIMM44	ENST00000923643.1		c.1260G>A	p.Ala420Ala	synonymous	Exon 13 of 13	ENSP00000593702.1
	TIMM44	ENST00000870121.1		c.1242G>A	p.Ala414Ala	synonymous	Exon 13 of 13	ENSP00000540180.1

Frequencies

GnomAD3 genomes AF: 0.000644 AC: 98 AN: 152122 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000525 AC: 130 AN: 247688 AF XY: 0.000535

Gnomad AFR exome AF: 0.000618

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.000894

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000607 AC: 886 AN: 1459640 Hom.: 1 Cov.: 32 AF XY: 0.000642 AC XY: 466 AN XY: 726196

African (AFR) AF: 0.000747 AC: 25 AN: 33454

American (AMR) AF: 0.000157 AC: 7 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86210

European-Finnish (FIN) AF: 0.000268 AC: 14 AN: 52172

Middle Eastern (MID) AF: 0.000199 AC: 1 AN: 5032

European-Non Finnish (NFE) AF: 0.000718 AC: 798 AN: 1111944

Other (OTH) AF: 0.000564 AC: 34 AN: 60280

GnomAD4 genome AF: 0.000644 AC: 98 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000564 AC XY: 42 AN XY: 74440

African (AFR) AF: 0.000602 AC: 25 AN: 41536

American (AMR) AF: 0.000523 AC: 8 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000568 Hom.: 0

Bravo AF: 0.000661

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	7.8
DANN	Benign	0.94
PhyloP100		-3.3
Mutation Taster		=100/0	polymorphism

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: rs138385134; hg19: chr19-7992159;