7-4911168-G-C

Position:

• chr7-4911168-G-C

Variant summary

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

The NM_198403.4(MMD2):​c.444C>G​(p.Ile148Met) 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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MMD2 NM_198403.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

Genes affected

MMD2 (HGNC:30133): (monocyte to macrophage differentiation associated 2) This gene encodes a member of the PAQR (progestin and adipoQ receptor) family. Members of this family are evolutionarily conserved with significant sequence identity to bacterial hemolysin-like proteins and are defined by a set of seven transmembrane domains. The protein encoded by this gene localizes to the Golgi apparatus to modulate Ras signaling. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jun 2012]

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=0.21626702).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MMD2	NM_198403.4	c.444C>G	p.Ile148Met	missense_variant	5/7	ENST00000401401.8	NP_940685.3
MMD2	NM_001100600.2	c.444C>G	p.Ile148Met	missense_variant	5/7		NP_001094070.1
MMD2	NM_001270375.2	c.444C>G	p.Ile148Met	missense_variant	5/8		NP_001257304.1
MMD2	NR_072989.2	n.668C>G		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MMD2	ENST00000401401.8	c.444C>G	p.Ile148Met	missense_variant	5/7	1	NM_198403.4	ENSP00000384141	P1
MMD2	ENST00000404774.7	c.444C>G	p.Ile148Met	missense_variant	5/7	1		ENSP00000384690
MMD2	ENST00000406755.5	c.444C>G	p.Ile148Met	missense_variant	5/8	1		ENSP00000385963
MMD2	ENST00000612910.1	c.444C>G	p.Ile148Met	missense_variant	5/7	5		ENSP00000484193

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2022

The c.444C>G (p.I148M) alteration is located in exon 5 (coding exon 5) of the MMD2 gene. This alteration results from a C to G substitution at nucleotide position 444, causing the isoleucine (I) at amino acid position 148 to be replaced by a methionine (M). 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	0.083
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.058	.;T;.;.
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.87	.;D;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;M;M
MutationTaster	Benign	0.95	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.1	N;N;N;.
REVEL	Benign	0.045
Sift	Benign	0.049	D;T;T;.
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.030, 0.13	.;B;B;.
Vest4		0.35
MutPred		0.46		Loss of catalytic residue at I148 (P = 0.0031);Loss of catalytic residue at I148 (P = 0.0031);Loss of catalytic residue at I148 (P = 0.0031);Loss of catalytic residue at I148 (P = 0.0031);
MVP		0.21
MPC		0.043
ClinPred		0.13	T
GERP RS		2.6
Varity_R		0.092
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-4950799;