Genetic Variant MAEL:p.Pro212His (chr1-167004291-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032858.3(MAEL):c.635C>A(p.Pro212His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,598,142 control chromosomes in the GnomAD database, including 64 homozygotes. 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 Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 35 hom., cov: 32)

Exomes 𝑓: 0.0011 ( 29 hom. )

Consequence

MAEL
NM_032858.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.459

Publications

4 publications found

Variant links:

Genes affected

MAEL (HGNC:25929): (maelstrom spermatogenic transposon silencer) Predicted to enable sequence-specific DNA binding activity. Predicted to be involved in gamete generation; negative regulation of macromolecule metabolic process; and piRNA metabolic process. Predicted to act upstream of or within several processes, including homologous chromosome pairing at meiosis; intrinsic apoptotic signaling pathway in response to DNA damage; and negative regulation of macromolecule metabolic process. Predicted to be located in piP-body. Predicted to be active in P granule and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

MAEL links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002958119).

BP6

Variant 1-167004291-C-A is Benign according to our data. Variant chr1-167004291-C-A is described in ClinVar as Benign. ClinVar VariationId is 780787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0116 (1766/152278) while in subpopulation AFR AF = 0.0407 (1692/41534). AF 95% confidence interval is 0.0391. There are 35 homozygotes in GnomAd4. There are 802 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032858.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAEL	NM_032858.3	MANE Select	c.635C>A	p.Pro212His	missense	Exon 6 of 12	NP_116247.1	A0A140VJP0
MAEL	NM_001286377.2		c.542C>A	p.Pro181His	missense	Exon 5 of 11	NP_001273306.1	Q96JY0-2
MAEL	NM_001286378.2		c.467C>A	p.Pro156His	missense	Exon 7 of 13	NP_001273307.1	E9JVC4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAEL	ENST00000367872.9	TSL:1 MANE Select	c.635C>A	p.Pro212His	missense	Exon 6 of 12	ENSP00000356846.4	Q96JY0-1
MAEL	ENST00000367870.6	TSL:1	c.542C>A	p.Pro181His	missense	Exon 5 of 11	ENSP00000356844.2	Q96JY0-2
MAEL	ENST00000622874.4	TSL:1	c.467C>A	p.Pro156His	missense	Exon 7 of 13	ENSP00000482771.1	E9JVC4

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1764

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0408

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00670

GnomAD2 exomes

AF:

0.00299

AC:

710

AN:

237422

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.0408

Gnomad AMR exome

AF:

0.00168

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000363

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00110

AC:

1587

AN:

1445864

Hom.:

Cov.:

AF XY:

0.000925

AC XY:

665

AN XY:

718646

show subpopulations

African (AFR)

AF:

0.0408

AC:

1331

AN:

32634

American (AMR)

AF:

0.00207

AC:

AN:

41530

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25626

East Asian (EAS)

AF:

0.00

AC:

AN:

39196

South Asian (SAS)

AF:

0.0000486

AC:

AN:

82306

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53226

Middle Eastern (MID)

AF:

0.00140

AC:

AN:

5712

European-Non Finnish (NFE)

AF:

0.0000199

AC:

AN:

1105922

Other (OTH)

AF:

0.00228

AC:

136

AN:

59712

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0116

AC:

1766

AN:

152278

Hom.:

Cov.:

AF XY:

0.0108

AC XY:

802

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0407

AC:

1692

AN:

41534

American (AMR)

AF:

0.00360

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68024

Other (OTH)

AF:

0.00663

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

176

265

353

441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00359

Hom.:

Bravo

AF:

0.0135

ESP6500AA

AF:

0.0395

AC:

174

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00383

AC:

465

Asia WGS

AF:

0.00375

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

Eigen

Benign

0.13

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.66

MetaRNN

Benign

0.0030

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

PhyloP100

0.46

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-4.4

REVEL

Benign

0.070

Sift

Benign

0.032

Sift4G

Benign

0.16

Polyphen

0.79

Vest4

0.65

MVP

0.69

MPC

0.72

ClinPred

0.048

GERP RS

3.7

Varity_R

0.17

gMVP

0.86

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over