1-167005351-C-T

Position:

• chr1-167005351-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP5_Moderate

The ENST00000367872.9(MAEL):​c.799C>T​(p.Arg267Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,384 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MAEL ENST00000367872.9 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.53

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-167005351-C-T is Pathogenic according to our data. Variant chr1-167005351-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3024483.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAEL	NM_032858.3	c.799C>T	p.Arg267Ter	stop_gained	8/12	ENST00000367872.9	NP_116247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAEL	ENST00000367872.9	c.799C>T	p.Arg267Ter	stop_gained	8/12	1	NM_032858.3	ENSP00000356846	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461384 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 726984

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Male infertility Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Institute of Reproductive Genetics, University of Münster

Feb 27, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Benign	0.66	D
MutationTaster	Benign	1.0	A;A
Vest4		0.92
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs898422350; hg19: chr1-166974588; COSMIC: COSV63112319; COSMIC: COSV63112319;