chr1-2629464-T-G

Variant names:

• chr1-2629464-T-G
• rs4648659
• NM_033467.4:c.21A>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_033467.4(MMEL1):​c.21A>C​(p.Pro7Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,528,842 control chromosomes in the GnomAD database, including 322,736 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P7P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.60 (27966 hom., cov: 33)
  • Exomes 𝑓: 0.65 (294770 hom.)
• Consequence: MMEL1 NM_033467.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.34
• Publications: 26 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]

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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 1-2629464-T-G is Benign according to our data. Variant chr1-2629464-T-G is described in ClinVar as Benign. ClinVar VariationId is 1303609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.34 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.676 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.21A>C	p.Pro7Pro	synonymous	Exon 2 of 24	NP_258428.2	Q495T6-1
	MMEL1-AS1	NR_183343.1		n.148+561T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMEL1	ENST00000378412.8	TSL:2 MANE Select	c.21A>C	p.Pro7Pro	synonymous	Exon 2 of 24	ENSP00000367668.3	Q495T6-1
	MMEL1	ENST00000502556.5	TSL:1	c.21A>C	p.Pro7Pro	synonymous	Exon 1 of 19	ENSP00000422492.1	Q495T6-3
	MMEL1	ENST00000504800.5	TSL:2	n.21A>C		non_coding_transcript_exon	Exon 1 of 23	ENSP00000425477.1	Q495T6-2

Frequencies

GnomAD3 genomes AF: 0.599 AC: 90774 AN: 151576 Hom.: 27941 Cov.: 33

Gnomad AFR AF: 0.473

Gnomad AMI AF: 0.846

Gnomad AMR AF: 0.573

Gnomad ASJ AF: 0.696

Gnomad EAS AF: 0.489

Gnomad SAS AF: 0.499

Gnomad FIN AF: 0.635

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.681

Gnomad OTH AF: 0.636

GnomAD2 exomes AF: 0.600 AC: 79953 AN: 133148 AF XY: 0.599

Gnomad AFR exome AF: 0.453

Gnomad AMR exome AF: 0.570

Gnomad ASJ exome AF: 0.695

Gnomad EAS exome AF: 0.481

Gnomad FIN exome AF: 0.642

Gnomad NFE exome AF: 0.675

Gnomad OTH exome AF: 0.626

GnomAD4 exome AF: 0.651 AC: 896409 AN: 1377148 Hom.: 294770 Cov.: 58 AF XY: 0.648 AC XY: 439755 AN XY: 678266

African (AFR) AF: 0.463 AC: 14151 AN: 30540

American (AMR) AF: 0.573 AC: 19710 AN: 34396

Ashkenazi Jewish (ASJ) AF: 0.694 AC: 16919 AN: 24374

East Asian (EAS) AF: 0.499 AC: 17381 AN: 34798

South Asian (SAS) AF: 0.524 AC: 41007 AN: 78250

European-Finnish (FIN) AF: 0.646 AC: 27868 AN: 43172

Middle Eastern (MID) AF: 0.699 AC: 3389 AN: 4850

European-Non Finnish (NFE) AF: 0.673 AC: 719990 AN: 1069678

Other (OTH) AF: 0.630 AC: 35994 AN: 57090

GnomAD4 genome AF: 0.599 AC: 90837 AN: 151694 Hom.: 27966 Cov.: 33 AF XY: 0.594 AC XY: 44044 AN XY: 74112

African (AFR) AF: 0.474 AC: 19619 AN: 41416

American (AMR) AF: 0.572 AC: 8732 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.696 AC: 2413 AN: 3468

East Asian (EAS) AF: 0.490 AC: 2518 AN: 5140

South Asian (SAS) AF: 0.499 AC: 2406 AN: 4824

European-Finnish (FIN) AF: 0.635 AC: 6681 AN: 10514

Middle Eastern (MID) AF: 0.658 AC: 192 AN: 292

European-Non Finnish (NFE) AF: 0.681 AC: 46180 AN: 67768

Other (OTH) AF: 0.630 AC: 1326 AN: 2106

Alfa AF: 0.646 Hom.: 13120

Bravo AF: 0.595

Asia WGS AF: 0.427 AC: 1485 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.21
DANN	Benign	0.37
PhyloP100		-2.3
PromoterAI		-0.036	Neutral
Mutation Taster		=298/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs4648659; hg19: chr1-2560903; COSMIC: COSV56519004; COSMIC: COSV56519004;