3-155160397-A-G

Variant names:

• chr3-155160397-A-G
• rs2108350900
• NM_007289.4:c.1609A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_007289.4(MME):​c.1609A>G​(p.Ser537Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,454,630 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S537R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: MME NM_007289.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.82
• Publications: 0 publications found

Genes affected

MME (HGNC:7154): (membrane metalloendopeptidase) The protein encoded by this gene is a type II transmembrane glycoprotein and a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). The encoded protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. This protein is not restricted to leukemic cells, however, and is found on a variety of normal tissues. The protein is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. [provided by RefSeq, Aug 2017]

MME-AS1 (HGNC:40376): (MME antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3813671).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007289.4. 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
	MME	NM_007289.4	MANE Select	c.1609A>G	p.Ser537Gly	missense	Exon 17 of 23	NP_009220.2	P08473
	MME	NM_000902.5		c.1609A>G	p.Ser537Gly	missense	Exon 17 of 23	NP_000893.2	P08473
	MME	NM_001354642.2		c.1609A>G	p.Ser537Gly	missense	Exon 17 of 23	NP_001341571.1	P08473

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MME	ENST00000360490.7	TSL:1 MANE Select	c.1609A>G	p.Ser537Gly	missense	Exon 17 of 23	ENSP00000353679.2	P08473
	MME	ENST00000615825.2	TSL:1	c.1699A>G	p.Ser567Gly	missense	Exon 18 of 24	ENSP00000478173.2	A0A7I2U302
	MME	ENST00000460393.6	TSL:1	c.1609A>G	p.Ser537Gly	missense	Exon 17 of 23	ENSP00000418525.1	P08473

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454630 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724152

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33284

American (AMR) AF: 0.00 AC: 0 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39550

South Asian (SAS) AF: 0.00 AC: 0 AN: 86092

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.04e-7 AC: 1 AN: 1105766

Other (OTH) AF: 0.00 AC: 0 AN: 60112

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.095	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Benign	0.066
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.052	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.027	D
Polyphen		0.15	B
Vest4		0.44
MutPred		0.53		Loss of glycosylation at S537 (P = 0.0254)
MVP		0.84
MPC		0.066
ClinPred		0.93	D
GERP RS		5.5
Varity_R		0.65
gMVP		0.78
Mutation Taster		=51/49	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2108350900; hg19: chr3-154878186;