1-2595307-A-G

Variant summary

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

The NM_033467.4(MMEL1):c.1553T>C(p.Met518Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,613,220 control chromosomes in the GnomAD database, including 125,158 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.46 (17617 hom., cov: 33)
  • Exomes 𝑓: 0.38 (107541 hom.)
• Consequence: MMEL1 NM_033467.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.27

Genes affected

MMEL1 (HGNC:14668): (membrane metalloendopeptidase like 1) The protein encoded by this gene is a member of the neutral endopeptidase (NEP) or membrane metallo-endopeptidase (MME) family. Family members play important roles in pain perception, arterial pressure regulation, phosphate metabolism and homeostasis. This protein is a type II transmembrane protein and is thought to be expressed as a secreted protein. This gene is expressed mainly in testis with weak expression in the brain, kidney, and heart. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.5405934E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.668 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MMEL1	NM_033467.4	c.1553T>C	p.Met518Thr	missense_variant	16/24	ENST00000378412.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MMEL1	ENST00000378412.8	c.1553T>C	p.Met518Thr	missense_variant	16/24	2	NM_033467.4	P1
MMEL1	ENST00000502556.5	c.1082T>C	p.Met361Thr	missense_variant	11/19	1
MMEL1	ENST00000504800.5	c.1553T>C	p.Met518Thr	missense_variant, NMD_transcript_variant	15/23	2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69614 AN: 151880 Hom.: 17575 Cov.: 33

Gnomad AFR AF: 0.675

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.309

Gnomad EAS AF: 0.513

Gnomad SAS AF: 0.516

Gnomad FIN AF: 0.385

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.406

GnomAD3 exomes AF: 0.412 AC: 103254 AN: 250746 Hom.: 22810 AF XY: 0.406 AC XY: 55097 AN XY: 135674

Gnomad AFR exome AF: 0.686

Gnomad AMR exome AF: 0.454

Gnomad ASJ exome AF: 0.301

Gnomad EAS exome AF: 0.506

Gnomad SAS exome AF: 0.509

Gnomad FIN exome AF: 0.378

Gnomad NFE exome AF: 0.336

Gnomad OTH exome AF: 0.385

GnomAD4 exome AF: 0.376 AC: 548880 AN: 1461222 Hom.: 107541 Cov.: 48 AF XY: 0.377 AC XY: 274098 AN XY: 726916

Gnomad4 AFR exome AF: 0.686

Gnomad4 AMR exome AF: 0.454

Gnomad4 ASJ exome AF: 0.308

Gnomad4 EAS exome AF: 0.501

Gnomad4 SAS exome AF: 0.498

Gnomad4 FIN exome AF: 0.373

Gnomad4 NFE exome AF: 0.350

Gnomad4 OTH exome AF: 0.396

GnomAD4 genome AF: 0.459 AC: 69707 AN: 151998 Hom.: 17617 Cov.: 33 AF XY: 0.462 AC XY: 34350 AN XY: 74320

Gnomad4 AFR AF: 0.675

Gnomad4 AMR AF: 0.468

Gnomad4 ASJ AF: 0.309

Gnomad4 EAS AF: 0.511

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.385

Gnomad4 NFE AF: 0.341

Gnomad4 OTH AF: 0.412

Alfa AF: 0.360 Hom.: 19651

Bravo AF: 0.467

TwinsUK AF: 0.358 AC: 1326

ALSPAC AF: 0.357 AC: 1376

ESP6500AA AF: 0.681 AC: 3002

ESP6500EA AF: 0.336 AC: 2892

ExAC AF: 0.413 AC: 50128

Asia WGS AF: 0.592 AC: 2058 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.046
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	0.0010
Dann	Benign	0.24
DEOGEN2	Benign	0.070	T;.
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.012	T;T
MetaRNN	Benign	0.0000025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N;N
REVEL	Benign	0.17
Sift	Benign	0.71	T;T
Sift4G	Benign	0.66	T;T
Polyphen		0.0	B;.
Vest4		0.050
MPC		0.20
ClinPred		0.00096	T
GERP RS		-5.5
Varity_R		0.033
gMVP		0.23

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: rs3748816; hg19: chr1-2526746; COSMIC: COSV56519828; COSMIC: COSV56519828;