rs375663463

Variant names:

• chr1-166992745-C-T
• rs375663463
• NM_032858.3:c.385C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032858.3(MAEL):​c.385C>T​(p.His129Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,458,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MAEL NM_032858.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.84
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33845448).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAEL	NM_032858.3	MANE Select	c.385C>T	p.His129Tyr	missense	Exon 4 of 12	NP_116247.1	A0A140VJP0
	MAEL	NM_001286377.2		c.292C>T	p.His98Tyr	missense	Exon 3 of 11	NP_001273306.1	Q96JY0-2
	MAEL	NM_001286378.2		c.217C>T	p.His73Tyr	missense	Exon 5 of 13	NP_001273307.1	E9JVC4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MAEL	ENST00000367872.9	TSL:1 MANE Select	c.385C>T	p.His129Tyr	missense	Exon 4 of 12	ENSP00000356846.4	Q96JY0-1
	MAEL	ENST00000367870.6	TSL:1	c.292C>T	p.His98Tyr	missense	Exon 3 of 11	ENSP00000356844.2	Q96JY0-2
	MAEL	ENST00000622874.4	TSL:1	c.217C>T	p.His73Tyr	missense	Exon 5 of 13	ENSP00000482771.1	E9JVC4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458996 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725758

African (AFR) AF: 0.00 AC: 0 AN: 33286

American (AMR) AF: 0.00 AC: 0 AN: 44200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39530

South Asian (SAS) AF: 0.00 AC: 0 AN: 85544

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53326

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111006

Other (OTH) AF: 0.00 AC: 0 AN: 60266

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.0091	T
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L
PhyloP100		2.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.99	N
REVEL	Benign	0.18
Sift	Benign	0.042	D
Sift4G	Benign	0.18	T
Polyphen		0.99	D
Vest4		0.59
MutPred		0.51		Gain of stability (P = 0.0053)
MVP		0.65
MPC		0.67
ClinPred		0.86	D
GERP RS		5.5
Varity_R		0.19
gMVP		0.46
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs375663463; hg19: chr1-166961982;