chr12-57801990-C-T

Variant names:

• chr12-57801990-C-T
• rs3816896
• NM_006576.4:c.2151+170G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006576.4(AVIL):​c.2151+170G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 152,064 control chromosomes in the GnomAD database, including 10,881 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.36 (10881 hom., cov: 32)
• Consequence: AVIL NM_006576.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.114
• Publications: 10 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: Labcorp Genetics (formerly Invitae), Orphanet
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-57801990-C-T is Benign according to our data. Variant chr12-57801990-C-T is described in ClinVar as Benign. ClinVar VariationId is 1231318.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.449 is higher than 0.05.

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.2151+170G>A		intron	N/A	NP_006567.3
	TSFM	NM_001172697.2		c.572-565C>T		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.2151+170G>A		intron	N/A	ENSP00000449239.2	O75366-1
	AVIL	ENST00000257861.7	TSL:1	c.2151+170G>A		intron	N/A	ENSP00000257861.3	O75366-1
	TSFM	ENST00000543727.5	TSL:1	c.572-565C>T		intron	N/A	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54808 AN: 151946 Hom.: 10886 Cov.: 32

Gnomad AFR AF: 0.215

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.345

Gnomad ASJ AF: 0.532

Gnomad EAS AF: 0.220

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.440

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.360 AC: 54790 AN: 152064 Hom.: 10881 Cov.: 32 AF XY: 0.356 AC XY: 26497 AN XY: 74332

African (AFR) AF: 0.215 AC: 8907 AN: 41486

American (AMR) AF: 0.345 AC: 5271 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.532 AC: 1845 AN: 3470

East Asian (EAS) AF: 0.220 AC: 1136 AN: 5174

South Asian (SAS) AF: 0.273 AC: 1317 AN: 4824

European-Finnish (FIN) AF: 0.386 AC: 4070 AN: 10548

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30808 AN: 67964

Other (OTH) AF: 0.438 AC: 921 AN: 2104

Alfa AF: 0.405 Hom.: 1649

Bravo AF: 0.349

Asia WGS AF: 0.243 AC: 847 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.7
DANN	Benign	0.47
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3816896; hg19: chr12-58195773; COSMIC: COSV57683260; COSMIC: COSV57683260;