1-167004291-C-A

Position:

• chr1-167004291-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.459

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAEL	NM_032858.3	c.635C>A	p.Pro212His	missense_variant	6/12	ENST00000367872.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAEL	ENST00000367872.9	c.635C>A	p.Pro212His	missense_variant	6/12	1	NM_032858.3	P1

Frequencies

GnomAD3 genomes AF: 0.0116 AC: 1764 AN: 152160 Hom.: 35 Cov.: 32

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

GnomAD3 exomes AF: 0.00299 AC: 710 AN: 237422 Hom.: 14 AF XY: 0.00199 AC XY: 255 AN XY: 128264

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 SAS exome AF: 0.0000739

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.: 29 Cov.: 30 AF XY: 0.000925 AC XY: 665 AN XY: 718646

Gnomad4 AFR exome AF: 0.0408

Gnomad4 AMR exome AF: 0.00207

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000486

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000199

Gnomad4 OTH exome AF: 0.00228

GnomAD4 genome AF: 0.0116 AC: 1766 AN: 152278 Hom.: 35 Cov.: 32 AF XY: 0.0108 AC XY: 802 AN XY: 74468

Gnomad4 AFR AF: 0.0407

Gnomad4 AMR AF: 0.00360

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.0135

ESP6500AA AF: 0.0395 AC: 174

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00383 AC: 465

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	.;.;T;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.66	T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	.;.;L;.
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-4.4	.;D;D;D
REVEL	Benign	0.070
Sift	Benign	0.032	.;D;T;D
Sift4G	Benign	0.16	T;T;T;T
Polyphen		0.79	.;.;P;.
Vest4		0.65
MVP		0.69
MPC		0.72
ClinPred		0.048	T
GERP RS		3.7
Varity_R		0.17
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs76161896; hg19: chr1-166973528; COSMIC: COSV99057620; COSMIC: COSV99057620;