1-2629402-C-A

Variant names:

• chr1-2629402-C-A
• rs780812154
• NM_033467.4:c.83G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033467.4(MMEL1):​c.83G>T​(p.Gly28Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,546,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: MMEL1 NM_033467.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.778

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]

MMEL1-AS1 (HGNC:40695): (MMEL1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08167049).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMEL1	NM_033467.4	c.83G>T	p.Gly28Val	missense_variant	Exon 2 of 24	ENST00000378412.8	NP_258428.2
MMEL1-AS1	NR_183343.1	n.148+499C>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMEL1	ENST00000378412.8	c.83G>T	p.Gly28Val	missense_variant	Exon 2 of 24	2	NM_033467.4	ENSP00000367668.3
MMEL1	ENST00000502556.5	c.83G>T	p.Gly28Val	missense_variant	Exon 1 of 19	1		ENSP00000422492.1
MMEL1	ENST00000504800.5	n.83G>T		non_coding_transcript_exon_variant	Exon 1 of 23	2		ENSP00000425477.1

Frequencies

GnomAD3 genomes AF: 0.000302 AC: 46 AN: 152120 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000229 AC: 33 AN: 144018 Hom.: 0 AF XY: 0.000286 AC XY: 22 AN XY: 76940

Gnomad AFR exome AF: 0.00120

Gnomad AMR exome AF: 0.0000815

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000914

Gnomad SAS exome AF: 0.000663

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000571

Gnomad OTH exome AF: 0.000712

GnomAD4 exome AF: 0.0000947 AC: 132 AN: 1394216 Hom.: 0 Cov.: 55 AF XY: 0.000109 AC XY: 75 AN XY: 687834

Gnomad4 AFR exome AF: 0.000798

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.000670

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000287

Gnomad4 OTH exome AF: 0.000190

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152238 Hom.: 0 Cov.: 34 AF XY: 0.000201 AC XY: 15 AN XY: 74444

Gnomad4 AFR AF: 0.000867

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000581

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000242

ExAC AF: 0.000193 AC: 14

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.83G>T (p.G28V) alteration is located in exon 2 (coding exon 1) of the MMEL1 gene. This alteration results from a G to T substitution at nucleotide position 83, causing the glycine (G) at amino acid position 28 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.036	N
LIST_S2	Benign	0.49	T;T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.082	T;T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	1.9	L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.9	N;N
REVEL	Uncertain	0.39
Sift	Uncertain	0.011	D;D
Sift4G	Uncertain	0.057	T;T
Polyphen		0.98	D;.
Vest4		0.30
MVP		0.74
MPC		0.22
ClinPred		0.012	T
GERP RS		-0.034
Varity_R		0.12
gMVP		0.72

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: rs780812154; hg19: chr1-2560841;