Variant 2-74581766-C-CA details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 9P and 4B. PVS1PP5BS2

The NM_001321739.2(M1AP):c.676_677insT(p.Trp226LeufsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.00333 in 1,614,024 control chromosomes in the GnomAD database, including 7 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 6 hom. )

Consequence

M1AP
NM_001321739.2 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 6.31

Variant links:

Genes affected

M1AP (HGNC:25183): (meiosis 1 associated protein) This gene encodes a protein that is likely to function in progression of meiosis. A similar protein in mouse plays a role in gametogenesis in both sexes. Alternate splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]

M1AP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-74581766-C-CA is Pathogenic according to our data. Variant chr2-74581766-C-CA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 805830.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=3, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
M1AP	NM_001321739.2 linkuse as main transcript	c.676_677insT	p.Trp226LeufsTer4	frameshift_variant	5/11	ENST00000421985.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
M1AP	ENST00000421985.2 linkuse as main transcript	c.676_677insT	p.Trp226LeufsTer4	frameshift_variant	5/11	2	NM_001321739.2	P4	Q8TC57-1

Frequencies

GnomAD3 genomes

AF:

0.00228

AC:

347

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000748

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00397

Gnomad OTH

AF:

0.00382

GnomAD3 exomes

AF:

0.00208

AC:

524

AN:

251434

Hom.:

AF XY:

0.00213

AC XY:

290

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00179

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000647

Gnomad NFE exome

AF:

0.00381

Gnomad OTH exome

AF:

0.00163

GnomAD4 exome

AF:

0.00344

AC:

5023

AN:

1461744

Hom.:

Cov.:

AF XY:

0.00335

AC XY:

2436

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00176

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000730

Gnomad4 NFE exome

AF:

0.00422

Gnomad4 OTH exome

AF:

0.00286

GnomAD4 genome

AF:

0.00228

AC:

347

AN:

152280

Hom.:

Cov.:

AF XY:

0.00196

AC XY:

146

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000746

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00397

Gnomad4 OTH

AF:

0.00378

Alfa

AF:

0.00313

Hom.:

Bravo

AF:

0.00211

EpiCase

AF:

0.00355

EpiControl

AF:

0.00368

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spermatogenic failure 48

Pathogenic:2Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 20, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 18, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 09, 2023	- -

Male infertility with azoospermia or oligozoospermia due to single gene mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Laan Lab, Human Genetics Research Group, University of Tartu

Sep 01, 2023

- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

M1AP: PVS1, PP4, PS3:Supporting, PS4:Supporting -

Non-obstructive azoospermia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Institute of Reproductive Genetics, University of Münster

May 11, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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