17-55421687-G-T

Variant names:

• chr17-55421687-G-T
• rs1269857146
• NM_012329.3:c.9C>A

Variant summary

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

The NM_012329.3(MMD):​c.9C>A​(p.Phe3Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000235 in 1,444,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MMD NM_012329.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51

Genes affected

MMD (HGNC:7153): (monocyte to macrophage differentiation associated) This protein is expressed by in vitro differentiated macrophages but not freshly isolated monocytes. Although sequence analysis identifies seven potential transmembrane domains, this protein has little homology to G-protein receptors and it has not been positively identified as a receptor. A suggested alternative function is that of an ion channel protein in maturing macrophages. [provided by RefSeq, Jul 2008]

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=0.06922096).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MMD	NM_012329.3	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 7	ENST00000262065.8	NP_036461.2
MMD	XM_047435708.1	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 5		XP_047291664.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MMD	ENST00000262065.8	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 7	1	NM_012329.3	ENSP00000262065.3
MMD	ENST00000649377.1	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 8			ENSP00000497849.1
MMD	ENST00000571578.1	c.9C>A	p.Phe3Leu	missense_variant	Exon 1 of 5	3		ENSP00000459202.1
MMD	ENST00000577038.1	n.111C>A		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000235 AC: 34 AN: 1444230 Hom.: 0 Cov.: 33 AF XY: 0.0000223 AC XY: 16 AN XY: 718630

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000308

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000318 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9C>A (p.F3L) alteration is located in exon 1 (coding exon 1) of the MMD gene. This alteration results from a C to A substitution at nucleotide position 9, causing the phenylalanine (F) at amino acid position 3 to be replaced by a leucine (L). 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	Uncertain	0.51
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.66	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	N;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.16	N;.;.
REVEL	Benign	0.14
Sift	Benign	1.0	T;.;.
Sift4G	Benign	1.0	T;.;T
Polyphen		0.0	B;.;.
Vest4		0.33
MutPred		0.19		Loss of methylation at K4 (P = 0.0369);Loss of methylation at K4 (P = 0.0369);Loss of methylation at K4 (P = 0.0369);
MVP		0.25
MPC		0.77
ClinPred		0.37	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.28
gMVP		0.49

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

Publications

LitVar

Other links and lift over

dbSNP: rs1269857146; hg19: chr17-53499048;