22-41699599-G-A

Position:

• chr22-41699599-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_152513.4(MEI1):​c.61G>A​(p.Ala21Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00366 in 1,612,704 control chromosomes in the GnomAD database, including 163 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (73 hom., cov: 34)
  • Exomes 𝑓: 0.0023 (90 hom.)
• Consequence: MEI1 NM_152513.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.621

Genes affected

MEI1 (HGNC:28613): (meiotic double-stranded break formation protein 1) Predicted to be involved in meiosis I. Predicted to act upstream of or within gamete generation; meiotic spindle organization; and meiotic telomere clustering. Implicated in gestational trophoblastic neoplasm. [provided by Alliance of Genome Resources, Apr 2022]

MEI1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020428002).
• BP6: Variant 22-41699599-G-A is Benign according to our data. Variant chr22-41699599-G-A is described in ClinVar as [Benign]. Clinvar id is 778952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0569 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MEI1	NM_152513.4	c.61G>A	p.Ala21Thr	missense_variant	1/31	ENST00000401548.8	NP_689726.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MEI1	ENST00000401548.8	c.61G>A	p.Ala21Thr	missense_variant	1/31	1	NM_152513.4	ENSP00000384115.3
MEI1	ENST00000540833	c.-720G>A		5_prime_UTR_variant	1/20	5		ENSP00000444225.1

Frequencies

GnomAD3 genomes AF: 0.0170 AC: 2595 AN: 152238 Hom.: 68 Cov.: 34

Gnomad AFR AF: 0.0584

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00563

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000485

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00484 AC: 1164 AN: 240586 Hom.: 30 AF XY: 0.00377 AC XY: 496 AN XY: 131454

Gnomad AFR exome AF: 0.0612

Gnomad AMR exome AF: 0.00359

Gnomad ASJ exome AF: 0.00365

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000689

Gnomad FIN exome AF: 0.000143

Gnomad NFE exome AF: 0.000554

Gnomad OTH exome AF: 0.00220

GnomAD4 exome AF: 0.00225 AC: 3287 AN: 1460348 Hom.: 90 Cov.: 31 AF XY: 0.00205 AC XY: 1491 AN XY: 726480

Gnomad4 AFR exome AF: 0.0640

Gnomad4 AMR exome AF: 0.00367

Gnomad4 ASJ exome AF: 0.00360

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000661

Gnomad4 FIN exome AF: 0.000132

Gnomad4 NFE exome AF: 0.000309

Gnomad4 OTH exome AF: 0.00640

GnomAD4 genome AF: 0.0172 AC: 2620 AN: 152356 Hom.: 73 Cov.: 34 AF XY: 0.0165 AC XY: 1226 AN XY: 74508

Gnomad4 AFR AF: 0.0589

Gnomad4 AMR AF: 0.00562

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000485

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00347 Hom.: 14

Bravo AF: 0.0196

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0565 AC: 221

ESP6500EA AF: 0.000850 AC: 7

ExAC AF: 0.00575 AC: 693

Asia WGS AF: 0.0130 AC: 46 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000949

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 11, 2018	- -

MEI1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.071	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.29	N
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0020	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.033
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.019	D
Polyphen		0.28	B
Vest4		0.26
MVP		0.16
MPC		0.19
ClinPred		0.0037	T
GERP RS		2.3
Varity_R		0.056
gMVP		0.16

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

Other links and lift over

dbSNP: rs73424975; hg19: chr22-42095603;