Genetic Variant ACTRT2:p.Ala6Thr (chr1-3021702-G-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_080431.5(ACTRT2):c.16G>A(p.Ala6Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,613,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 0 hom. )

Consequence

ACTRT2
NM_080431.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.263

Variant links:

Genes affected

ACTRT2 (HGNC:24026): (actin related protein T2) The protein encoded by this intronless gene belongs to the actin family. Studies have shown that this protein may be involved in cytoskeletal organization similar to other cytoplasmic actin-related protein (ARP) subfamily members. Antibody raised against the human protein has been used to detect the protein by immunoblotting and immunofluorescence microscopy, demonstrating its specific synthesis in the testis, late in spermatid differentiation, and its localization in the calyx. [provided by RefSeq, Jul 2008]

ACTRT2 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.031931907).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTRT2	NM_080431.5 link	c.16G>A	p.Ala6Thr	missense_variant	Exon 1 of 1	ENST00000378404.4	NP_536356.3	Q8TDY3Q96LK1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTRT2	ENST00000378404.4 link	c.16G>A	p.Ala6Thr	missense_variant	Exon 1 of 1	6	NM_080431.5	ENSP00000367658.2		Q8TDY3

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000204

AC:

AN:

250286

Hom.:

AF XY:

0.000229

AC XY:

AN XY:

135398

show subpopulations

Gnomad AFR exome

AF:

0.000187

Gnomad AMR exome

AF:

0.000435

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000229

Gnomad FIN exome

AF:

0.0000463

Gnomad NFE exome

AF:

0.000203

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000220

AC:

322

AN:

1461154

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

726836

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000291

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000247

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000151

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.000168

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000217

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.16G>A (p.A6T) alteration is located in exon 1 (coding exon 1) of the ACTRT2 gene. This alteration results from a G to A substitution at nucleotide position 16, causing the alanine (A) at amino acid position 6 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.38

CADD

Benign

0.23

DANN

Benign

0.96

DEOGEN2

Benign

0.044

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.020

LIST_S2

Benign

0.10

M_CAP

Benign

0.041

MetaRNN

Benign

0.032

MetaSVM

Uncertain

-0.22

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.28

REVEL

Benign

0.20

Sift

Benign

0.085

Sift4G

Benign

0.71

Polyphen

0.0020

Vest4

0.021

MVP

0.43

MPC

0.12

ClinPred

0.0054

GERP RS

-2.7

Varity_R

0.036

gMVP

0.071

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over