12-8941939-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
M6PR	NM_002355.4	c.713A>G	p.Asp238Gly	missense_variant, splice_region_variant	Exon 7 of 7	ENST00000000412.8	NP_002346.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
M6PR	ENST00000000412.8	c.713A>G	p.Asp238Gly	missense_variant, splice_region_variant	Exon 7 of 7	1	NM_002355.4	ENSP00000000412.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 05, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.713A>G (p.D238G) alteration is located in exon 7 (coding exon 6) of the M6PR gene. This alteration results from a A to G substitution at nucleotide position 713, causing the aspartic acid (D) at amino acid position 238 to be replaced by a glycine (G). 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	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;D;T
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.90	D;D;D
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.7	.;M;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-5.3	.;D;D
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	.;D;D
Sift4G	Uncertain	0.017	D;D;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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-9094535;