chr12-57801221-A-G

Variant names:

• chr12-57801221-A-G
• rs116275535
• NM_006576.4:c.2152-9T>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006576.4(AVIL):​c.2152-9T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000516 in 1,611,828 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0028 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: AVIL NM_006576.4 intron
• Scores: Splicing: ADA: 0.0004423
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.315
• Publications: 0 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 12-57801221-A-G is Benign according to our data. Variant chr12-57801221-A-G is described in ClinVar as Benign. ClinVar VariationId is 734180.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown gene

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.2152-9T>C		intron	N/A	NP_006567.3
	TSFM	NM_001172697.2		c.572-1334A>G		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.2152-9T>C		intron	N/A	ENSP00000449239.2	O75366-1
	AVIL	ENST00000257861.7	TSL:1	c.2152-9T>C		intron	N/A	ENSP00000257861.3	O75366-1
	TSFM	ENST00000543727.5	TSL:1	c.572-1334A>G		intron	N/A	ENSP00000439342.1	P43897-4

Frequencies

GnomAD3 genomes AF: 0.00282 AC: 429 AN: 152148 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00964

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000655 AC: 164 AN: 250406 AF XY: 0.000450

Gnomad AFR exome AF: 0.00884

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.000982

GnomAD4 exome AF: 0.000273 AC: 399 AN: 1459562 Hom.: 2 Cov.: 29 AF XY: 0.000234 AC XY: 170 AN XY: 726236

African (AFR) AF: 0.00930 AC: 311 AN: 33430

American (AMR) AF: 0.000649 AC: 29 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39628

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53070

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5762

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110420

Other (OTH) AF: 0.000730 AC: 44 AN: 60288

GnomAD4 genome AF: 0.00284 AC: 432 AN: 152266 Hom.: 2 Cov.: 32 AF XY: 0.00275 AC XY: 205 AN XY: 74444

African (AFR) AF: 0.00968 AC: 402 AN: 41530

American (AMR) AF: 0.00131 AC: 20 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68036

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00109 Hom.: 0

Bravo AF: 0.00308

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	11
DANN	Benign	0.92
PhyloP100		0.32
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00044
dbscSNV1_RF	Benign	0.17
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: rs116275535; hg19: chr12-58195004;