1-2595307-A-C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033467.4(MMEL1):​c.1553T>G​(p.Met518Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 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: not found (cov: 33)
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03729692).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMEL1	NM_033467.4	c.1553T>G	p.Met518Arg	missense_variant	Exon 16 of 24	ENST00000378412.8	NP_258428.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMEL1	ENST00000378412.8	c.1553T>G	p.Met518Arg	missense_variant	Exon 16 of 24	2	NM_033467.4	ENSP00000367668.3
MMEL1	ENST00000502556.5	c.1082T>G	p.Met361Arg	missense_variant	Exon 11 of 19	1		ENSP00000422492.1
MMEL1	ENST00000504800.5	n.1553T>G		non_coding_transcript_exon_variant	Exon 15 of 23	2		ENSP00000425477.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 48

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 49039

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	0.0010
DANN	Benign	0.33
DEOGEN2	Benign	0.078	T;.
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.032	T;T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.037	T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.7	N;.
PhyloP100		-2.3
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.37	N;N
REVEL	Benign	0.18
Sift	Benign	0.56	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0	B;.
Vest4		0.15
MutPred		0.40		Gain of solvent accessibility (P = 6e-04);.;
MVP		0.23
MPC		0.26
ClinPred		0.050	T
GERP RS		-5.5
Varity_R		0.10
gMVP		0.51
Mutation Taster		=100/0	polymorphism

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;