chr12-57799665-T-A

Variant names:

• chr12-57799665-T-A
• rs11172344
• NM_006576.4:c.2346+130A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006576.4(AVIL):​c.2346+130A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AVIL NM_006576.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• Publications: 24 publications found

Genes affected

AVIL (HGNC:14188): (advillin) The protein encoded by this gene is a member of the gelsolin/villin family of actin regulatory proteins. This protein has structural similarity to villin. It binds actin and may play a role in the development of neuronal cells that form ganglia. [provided by RefSeq, Jul 2008]

TSFM (HGNC:12367): (Ts translation elongation factor, mitochondrial) This gene encodes a mitochondrial translation elongation factor. The encoded protein is an enzyme that catalyzes the exchange of guanine nucleotides on the translation elongation factor Tu during the elongation step of mitchondrial protein translation. Mutations in this gene are associated with combined oxidative phosphorylation deficiency-3 syndrome. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

TSFM Gene-Disease associations (from GenCC):

• mitochondrial disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• fatal mitochondrial disease due to combined oxidative phosphorylation defect type 3

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006576.4. 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
	AVIL	NM_006576.4	MANE Select	c.2346+130A>T		intron	N/A	NP_006567.3
	TSFM	NM_001172697.2		c.572-2890T>A		intron	N/A	NP_001166168.1	P43897-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AVIL	ENST00000549994.2	TSL:4 MANE Select	c.2346+130A>T		intron	N/A	ENSP00000449239.2	O75366-1
	AVIL	ENST00000257861.7	TSL:1	c.2346+130A>T		intron	N/A	ENSP00000257861.3	O75366-1
	TSFM	ENST00000543727.5	TSL:1	c.572-2890T>A		intron	N/A	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1183892 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 589022

African (AFR) AF: 0.00 AC: 0 AN: 26818

American (AMR) AF: 0.00 AC: 0 AN: 30084

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19552

East Asian (EAS) AF: 0.00 AC: 0 AN: 37948

South Asian (SAS) AF: 0.00 AC: 0 AN: 66280

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3406

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 913296

Other (OTH) AF: 0.00 AC: 0 AN: 50346

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	5.3
DANN	Benign	0.71
PhyloP100		0.32

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: rs11172344; hg19: chr12-58193448;