Genetic Variant ACTRT1:p.Lys90Gln (chrX-128051939-T-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_138289.4(ACTRT1):c.268A>C(p.Lys90Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,098,126 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. 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: not found (cov: 22)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

ACTRT1
NM_138289.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.929

Publications

0 publications found

Variant links:

Genes affected

ACTRT1 (HGNC:24027): (actin related protein T1) This gene encodes a protein related to the cytoskeletal protein beta-actin. This protein is a major component of the calyx in the perinuclear theca of mammalian sperm heads, and it therefore likely functions in spermatid formation. This gene is intronless and is similar to a related gene located on chromosome 1. A related pseudogene has also been identified approximately 75 kb downstream of this gene on chromosome X. [provided by RefSeq, May 2010]

ACTRT1 links:

ENSG00000225689 (HGNC:):

ENSG00000225689 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17918772).

BS2

High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTRT1	NM_138289.4 link	c.268A>C	p.Lys90Gln	missense_variant	Exon 1 of 1	ENST00000371124.5	NP_612146.1	Q8TDG2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACTRT1	ENST00000371124.5 link	c.268A>C	p.Lys90Gln	missense_variant	Exon 1 of 1	6	NM_138289.4	ENSP00000360165.3		Q8TDG2
ENSG00000225689	ENST00000660383.1 link	n.1329-24586A>C		intron_variant	Intron 10 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

183169

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1098126

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

363480

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.00

AC:

AN:

35203

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30133

South Asian (SAS)

AF:

0.00

AC:

AN:

54122

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.0000131

AC:

AN:

842123

Other (OTH)

AF:

0.0000217

AC:

AN:

46091

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 16, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.268A>C (p.K90Q) alteration is located in exon 1 (coding exon 1) of the ACTRT1 gene. This alteration results from a A to C substitution at nucleotide position 268, causing the lysine (K) at amino acid position 90 to be replaced by a glutamine (Q). 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

0.093

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Benign

-0.36

CADD

Benign

9.2

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.27

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.83

M_CAP

Benign

0.021

MetaRNN

Benign

0.18

MetaSVM

Uncertain

0.090

MutationAssessor

Benign

0.45

PhyloP100

0.93

PrimateAI

Benign

0.30

PROVEAN

Benign

-0.74

REVEL

Benign

0.23

Sift

Benign

0.081

Sift4G

Benign

0.11

Polyphen

0.030

Vest4

0.048

MutPred

0.48

Loss of methylation at K90 (P = 2e-04);

MVP

0.92

MPC

0.19

ClinPred

0.051

GERP RS

0.12

PromoterAI

-0.019

Neutral

(source)

Varity_R

0.12

gMVP

0.35

Mutation Taster

=89/11

polymorphism

(source)

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

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X-128051939-T-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over