1-2595307-A-G

Variant names:

• chr1-2595307-A-G
• rs3748816
• NM_033467.4:c.1553T>C

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 124 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_033467.4. 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
	MMEL1	NM_033467.4	MANE Select	c.1553T>C	p.Met518Thr	missense	Exon 16 of 24	NP_258428.2	Q495T6-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMEL1	ENST00000378412.8	TSL:2 MANE Select	c.1553T>C	p.Met518Thr	missense	Exon 16 of 24	ENSP00000367668.3	Q495T6-1
	MMEL1	ENST00000502556.5	TSL:1	c.1082T>C	p.Met361Thr	missense	Exon 11 of 19	ENSP00000422492.1	Q495T6-3
	MMEL1	ENST00000504800.5	TSL:2	n.1553T>C		non_coding_transcript_exon	Exon 15 of 23	ENSP00000425477.1	Q495T6-2

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

GnomAD2 exomes AF: 0.412 AC: 103254 AN: 250746 AF XY: 0.406

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 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

African (AFR) AF: 0.686 AC: 22972 AN: 33474

American (AMR) AF: 0.454 AC: 20298 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 8034 AN: 26120

East Asian (EAS) AF: 0.501 AC: 19876 AN: 39692

South Asian (SAS) AF: 0.498 AC: 42940 AN: 86232

European-Finnish (FIN) AF: 0.373 AC: 19834 AN: 53140

Middle Eastern (MID) AF: 0.327 AC: 1883 AN: 5766

European-Non Finnish (NFE) AF: 0.350 AC: 389104 AN: 1111726

Other (OTH) AF: 0.396 AC: 23939 AN: 60378

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

African (AFR) AF: 0.675 AC: 28008 AN: 41496

American (AMR) AF: 0.468 AC: 7154 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.309 AC: 1070 AN: 3466

East Asian (EAS) AF: 0.511 AC: 2631 AN: 5144

South Asian (SAS) AF: 0.516 AC: 2482 AN: 4812

European-Finnish (FIN) AF: 0.385 AC: 4072 AN: 10578

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.341 AC: 23177 AN: 67896

Other (OTH) AF: 0.412 AC: 870 AN: 2114

Alfa AF: 0.378 Hom.: 49039

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 v4.9

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
MetaRNN	Benign	0.0000025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.3	N
PhyloP100		-2.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.17
Sift	Benign	0.71	T
Sift4G	Benign	0.66	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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