chr3-155083948-A-G

Variant names:

• chr3-155083948-A-G
• rs3773905
• NM_007289.4:c.-10-210A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007289.4(MME):​c.-10-210A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.206 in 530,314 control chromosomes in the GnomAD database, including 11,756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3500 hom., cov: 32)
  • Exomes 𝑓: 0.20 (8256 hom.)
• Consequence: MME NM_007289.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.08
• 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 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease axonal type 2T

  Inheritance: SD, AR, AD Classification: DEFINITIVE, STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen
• MME-related autosomal dominant Charcot Marie Tooth disease type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• spinocerebellar ataxia 43

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• Charcot-Marie-Tooth disease type 2T

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• congenital membranous nephropathy due to maternal anti-neutral endopeptidase alloimmunization

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 3-155083948-A-G is Benign according to our data. Variant chr3-155083948-A-G is described in ClinVar as [Benign]. Clinvar id is 1258480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MME	NM_007289.4	c.-10-210A>G		intron_variant	Intron 1 of 22	ENST00000360490.7	NP_009220.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MME	ENST00000360490.7	c.-10-210A>G		intron_variant	Intron 1 of 22	1	NM_007289.4	ENSP00000353679.2

Frequencies

GnomAD3 genomes AF: 0.213 AC: 32407 AN: 152024 Hom.: 3495 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.0899

Gnomad AMR AF: 0.187

Gnomad ASJ AF: 0.245

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.186

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.216

Gnomad OTH AF: 0.224

GnomAD4 exome AF: 0.203 AC: 76787 AN: 378172 Hom.: 8256 Cov.: 4 AF XY: 0.201 AC XY: 40501 AN XY: 201188

African (AFR) AF: 0.231 AC: 2542 AN: 10994

American (AMR) AF: 0.158 AC: 2508 AN: 15922

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 2736 AN: 11426

East Asian (EAS) AF: 0.138 AC: 3438 AN: 24966

South Asian (SAS) AF: 0.177 AC: 7360 AN: 41604

European-Finnish (FIN) AF: 0.186 AC: 3981 AN: 21358

Middle Eastern (MID) AF: 0.266 AC: 424 AN: 1596

European-Non Finnish (NFE) AF: 0.215 AC: 49184 AN: 228620

Other (OTH) AF: 0.213 AC: 4614 AN: 21686

GnomAD4 genome AF: 0.213 AC: 32420 AN: 152142 Hom.: 3500 Cov.: 32 AF XY: 0.211 AC XY: 15696 AN XY: 74384

African (AFR) AF: 0.237 AC: 9830 AN: 41476

American (AMR) AF: 0.187 AC: 2855 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.245 AC: 850 AN: 3472

East Asian (EAS) AF: 0.152 AC: 786 AN: 5182

South Asian (SAS) AF: 0.171 AC: 823 AN: 4826

European-Finnish (FIN) AF: 0.186 AC: 1969 AN: 10584

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.216 AC: 14673 AN: 67992

Other (OTH) AF: 0.224 AC: 473 AN: 2110

Alfa AF: 0.218 Hom.: 1723

Bravo AF: 0.212

Asia WGS AF: 0.165 AC: 573 AN: 3474

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.3
DANN	Benign	0.77
PhyloP100		1.1
PromoterAI		0.0038	Neutral
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: rs3773905; hg19: chr3-154801737;