7-4909922-C-T

Variant names:

• chr7-4909922-C-T
• rs373364937
• NM_198403.4:c.496G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_198403.4(MMD2):​c.496G>A​(p.Val166Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,900 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (1 hom.)
• Consequence: MMD2 NM_198403.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.203
• Publications: 3 publications found

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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012984604).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_198403.4. 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
	MMD2	NM_198403.4	MANE Select	c.496G>A	p.Val166Ile	missense	Exon 6 of 7	NP_940685.3
	MMD2	NM_001100600.2		c.568G>A	p.Val190Ile	missense	Exon 6 of 7	NP_001094070.1	Q8IY49-1
	MMD2	NM_001270375.2		c.496G>A	p.Val166Ile	missense	Exon 6 of 8	NP_001257304.1	Q8IY49-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MMD2	ENST00000401401.8	TSL:1 MANE Select	c.496G>A	p.Val166Ile	missense	Exon 6 of 7	ENSP00000384141.3	Q8IY49-2
	MMD2	ENST00000404774.7	TSL:1	c.568G>A	p.Val190Ile	missense	Exon 6 of 7	ENSP00000384690.3	Q8IY49-1
	MMD2	ENST00000406755.5	TSL:1	c.496G>A	p.Val166Ile	missense	Exon 6 of 8	ENSP00000385963.1	Q8IY49-3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000161 AC: 40 AN: 248542 AF XY: 0.000119

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000160

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000210 AC: 307 AN: 1461628 Hom.: 1 Cov.: 31 AF XY: 0.000232 AC XY: 169 AN XY: 727094

African (AFR) AF: 0.00140 AC: 47 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000217 AC: 241 AN: 1111868

Other (OTH) AF: 0.000116 AC: 7 AN: 60372

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74452

African (AFR) AF: 0.000987 AC: 41 AN: 41560

American (AMR) AF: 0.000916 AC: 14 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000230 Hom.: 0

Bravo AF: 0.000465

ESP6500AA AF: 0.000737 AC: 3

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.000190 AC: 23

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.5
DANN	Benign	0.81
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.53	N
PhyloP100		-0.20
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.0050
Sift	Benign	0.33	T
Sift4G	Benign	0.40	T
Polyphen		0.028	B
Vest4		0.26
MVP		0.072
MPC		0.036
ClinPred		0.0029	T
GERP RS		-1.4
Varity_R		0.019
gMVP		0.23
Mutation Taster		=95/5	polymorphism

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: rs373364937; hg19: chr7-4949553; COSMIC: COSV68660829;