chr12-8941939-T-C

Variant names:

• chr12-8941939-T-C
• NM_002355.4:c.713A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002355.4(M6PR):​c.713A>G​(p.Asp238Gly) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: M6PR NM_002355.4 missense, splice_region
• Scores: Splicing: ADA: 0.8093
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 0 publications found

Genes affected

M6PR (HGNC:6752): (mannose-6-phosphate receptor, cation dependent) This gene encodes a member of the P-type lectin family. P-type lectins play a critical role in lysosome function through the specific transport of mannose-6-phosphate-containing acid hydrolases from the Golgi complex to lysosomes. The encoded protein functions as a homodimer and requires divalent cations for ligand binding. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. A pseudogene of this gene is located on the long arm of chromosome X. [provided by RefSeq, May 2011]

PHC1 (HGNC:3182): (polyhomeotic homolog 1) This gene is a homolog of the Drosophila polyhomeotic gene, which is a member of the Polycomb group of genes. The gene product is a component of a multimeric protein complex that contains EDR2 and the vertebrate Polycomb protein BMH1. The gene product, the EDR2 protein, and the Drosophila polyhomeotic protein share 2 highly conserved domains, named homology domains I and II. These domains are involved in protein-protein interactions and may mediate heterodimerization of the protein encoded by this gene and the EDR2 protein. [provided by RefSeq, Jul 2008]

PHC1 Gene-Disease associations (from GenCC):

• autosomal recessive primary microcephaly

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• microcephaly 11, primary, autosomal recessive

  Inheritance: AR Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002355.4. 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
	M6PR	NM_002355.4	MANE Select	c.713A>G	p.Asp238Gly	missense splice_region	Exon 7 of 7	NP_002346.1	P20645
	M6PR	NM_001414320.1		c.713A>G	p.Asp238Gly	missense splice_region	Exon 8 of 8	NP_001401249.1	P20645
	M6PR	NM_001414331.1		c.713A>G	p.Asp238Gly	missense splice_region	Exon 7 of 7	NP_001401260.1	P20645

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	M6PR	ENST00000000412.8	TSL:1 MANE Select	c.713A>G	p.Asp238Gly	missense splice_region	Exon 7 of 7	ENSP00000000412.3	P20645
	M6PR	ENST00000891555.1		c.713A>G	p.Asp238Gly	missense splice_region	Exon 7 of 7	ENSP00000561614.1
	M6PR	ENST00000891556.1		c.713A>G	p.Asp238Gly	missense splice_region	Exon 7 of 7	ENSP00000561615.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

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	Pathogenic	0.92
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.5
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.017	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.86		Loss of stability (P = 0.0189)
MVP		0.65
MPC		1.2
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.87
Mutation Taster		=31/69	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Pathogenic	0.85
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

Other links and lift over

hg19: chr12-9094535;