X-128051980-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_138289.4(ACTRT1):c.227G>A(p.Arg76His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000164 in 1,098,022 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R76C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 10 hem. )

Consequence

ACTRT1
NM_138289.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.33

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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.3197732).

BS2

High Hemizygotes in GnomAdExome4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACTRT1	NM_138289.4 link	c.227G>A	p.Arg76His	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.227G>A	p.Arg76His	missense_variant	Exon 1 of 1	6	NM_138289.4	ENSP00000360165.3		Q8TDG2
ENSG00000225689	ENST00000660383.1 link	n.1329-24627G>A		intron_variant	Intron 10 of 10

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000273

AC:

AN:

183004

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000730

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1098022

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

363378

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26403

American (AMR)

AF:

0.0000852

AC:

AN:

35196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19379

East Asian (EAS)

AF:

0.00

AC:

AN:

30132

South Asian (SAS)

AF:

0.000203

AC:

AN:

54111

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00000475

AC:

AN:

842050

Other (OTH)

AF:

0.00

AC:

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.227G>A (p.R76H) alteration is located in exon 1 (coding exon 1) of the ACTRT1 gene. This alteration results from a G to A substitution at nucleotide position 227, causing the arginine (R) at amino acid position 76 to be replaced by a histidine (H). 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

0.096

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.29

CADD

Benign

5.3

(source)

DANN

Benign

0.60

DEOGEN2

Benign

0.21

FATHMM_MKL

Benign

0.34

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.059

MetaRNN

Benign

0.32

MetaSVM

Uncertain

0.042

MutationAssessor

Benign

0.57

PhyloP100

1.3

PrimateAI

Benign

0.25

PROVEAN

Benign

1.1

REVEL

Uncertain

0.33

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.83

Vest4

0.032

MutPred

0.61

Gain of catalytic residue at G77 (P = 0.0718);

MVP

0.95

MPC

0.048

ClinPred

0.062

GERP RS

2.0

PromoterAI

0.0047

Neutral

(source)

Varity_R

0.057

gMVP

0.24

Mutation Taster

=98/2

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-128051980-C-T

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