chr1-166989473-T-G

Variant names:

• chr1-166989473-T-G
• rs11578336
• NM_032858.3:c.121T>G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032858.3(MAEL):​c.121T>G​(p.Ser41Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.243 in 1,584,168 control chromosomes in the GnomAD database, including 47,874 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.26 (5571 hom., cov: 32)
  • Exomes 𝑓: 0.24 (42303 hom.)
• Consequence: MAEL NM_032858.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.440

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.971393E-4).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.359 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAEL	NM_032858.3	c.121T>G	p.Ser41Ala	missense_variant	Exon 1 of 12	ENST00000367872.9	NP_116247.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAEL	ENST00000367872.9	c.121T>G	p.Ser41Ala	missense_variant	Exon 1 of 12	1	NM_032858.3	ENSP00000356846.4
MAEL	ENST00000367870.6	c.121T>G	p.Ser41Ala	missense_variant	Exon 1 of 11	1		ENSP00000356844.2
MAEL	ENST00000622874	c.-48T>G		5_prime_UTR_variant	Exon 2 of 13	1		ENSP00000482771.1
MAEL	ENST00000447624.1	c.121T>G	p.Ser41Ala	missense_variant	Exon 1 of 9	3		ENSP00000402143.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39749 AN: 152008 Hom.: 5564 Cov.: 32

Gnomad AFR AF: 0.364

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.195

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.243

Gnomad OTH AF: 0.232

GnomAD3 exomes AF: 0.216 AC: 43220 AN: 200332 Hom.: 4824 AF XY: 0.214 AC XY: 22951 AN XY: 107154

Gnomad AFR exome AF: 0.365

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.224

Gnomad SAS exome AF: 0.190

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.234

Gnomad OTH exome AF: 0.209

GnomAD4 exome AF: 0.241 AC: 345282 AN: 1432042 Hom.: 42303 Cov.: 33 AF XY: 0.238 AC XY: 168956 AN XY: 709154

Gnomad4 AFR exome AF: 0.368

Gnomad4 AMR exome AF: 0.146

Gnomad4 ASJ exome AF: 0.171

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.192

Gnomad4 FIN exome AF: 0.202

Gnomad4 NFE exome AF: 0.249

Gnomad4 OTH exome AF: 0.234

GnomAD4 genome AF: 0.261 AC: 39779 AN: 152126 Hom.: 5571 Cov.: 32 AF XY: 0.257 AC XY: 19087 AN XY: 74376

Gnomad4 AFR AF: 0.364

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.240

Gnomad4 SAS AF: 0.195

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.243

Gnomad4 OTH AF: 0.229

Alfa AF: 0.239 Hom.: 11107

Bravo AF: 0.265

TwinsUK AF: 0.260 AC: 964

ALSPAC AF: 0.254 AC: 980

ESP6500AA AF: 0.356 AC: 1568

ESP6500EA AF: 0.245 AC: 2107

ExAC AF: 0.196 AC: 23375

Asia WGS AF: 0.178 AC: 621 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.91
DANN	Benign	0.17
DEOGEN2	Benign	0.016	.;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0058	N
LIST_S2	Benign	0.035	T;T;T
MetaRNN	Benign	0.00090	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.90	N;N;.
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.025
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.71	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.11
MPC		0.15
ClinPred		0.00032	T
GERP RS		2.5
Varity_R		0.041
gMVP		0.12

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: rs11578336; hg19: chr1-166958710; COSMIC: COSV63304308; COSMIC: COSV63304308;