Genetic Variant NM_002355.4:c.343+112G>C (chr12-8945306-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002355.4(M6PR):c.343+112G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0558 in 1,122,512 control chromosomes in the GnomAD database, including 2,708 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.046 ( 312 hom., cov: 33)

Exomes 𝑓: 0.057 ( 2396 hom. )

Consequence

M6PR
NM_002355.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0940

Publications

3 publications found

Variant links:

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]

M6PR links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
M6PR	NM_002355.4	MANE Select	c.343+112G>C	intron	N/A	NP_002346.1	P20645
M6PR	NM_001414320.1		c.343+112G>C	intron	N/A	NP_001401249.1	P20645
M6PR	NM_001414331.1		c.343+112G>C	intron	N/A	NP_001401260.1	P20645

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
M6PR	ENST00000000412.8	TSL:1 MANE Select	c.343+112G>C	intron	N/A	ENSP00000000412.3	P20645
M6PR	ENST00000891555.1		c.343+112G>C	intron	N/A	ENSP00000561614.1
M6PR	ENST00000891556.1		c.343+112G>C	intron	N/A	ENSP00000561615.1

Frequencies

GnomAD3 genomes

AF:

0.0465

AC:

7072

AN:

152124

Hom.:

314

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.0504

Gnomad AMR

AF:

0.0522

Gnomad ASJ

AF:

0.0562

Gnomad EAS

AF:

0.242

Gnomad SAS

AF:

0.0308

Gnomad FIN

AF:

0.0316

Gnomad MID

AF:

0.0601

Gnomad NFE

AF:

0.0541

Gnomad OTH

AF:

0.0693

GnomAD4 exome

AF:

0.0573

AC:

55603

AN:

970270

Hom.:

2396

Cov.:

AF XY:

0.0563

AC XY:

27800

AN XY:

493578

show subpopulations

African (AFR)

AF:

0.00966

AC:

225

AN:

23300

American (AMR)

AF:

0.0428

AC:

1555

AN:

36312

Ashkenazi Jewish (ASJ)

AF:

0.0633

AC:

1199

AN:

18938

East Asian (EAS)

AF:

0.239

AC:

8846

AN:

37078

South Asian (SAS)

AF:

0.0229

AC:

1500

AN:

65458

European-Finnish (FIN)

AF:

0.0328

AC:

1651

AN:

50332

Middle Eastern (MID)

AF:

0.0493

AC:

153

AN:

3104

European-Non Finnish (NFE)

AF:

0.0548

AC:

37963

AN:

692218

Other (OTH)

AF:

0.0577

AC:

2511

AN:

43530

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

2498

4996

7495

9993

12491

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1244

2488

3732

4976

6220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0464

AC:

7062

AN:

152242

Hom.:

312

Cov.:

AF XY:

0.0475

AC XY:

3537

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0109

AC:

452

AN:

41534

American (AMR)

AF:

0.0522

AC:

798

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0562

AC:

195

AN:

3470

East Asian (EAS)

AF:

0.240

AC:

1244

AN:

5176

South Asian (SAS)

AF:

0.0307

AC:

148

AN:

4828

European-Finnish (FIN)

AF:

0.0316

AC:

335

AN:

10604

Middle Eastern (MID)

AF:

0.0544

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0541

AC:

3681

AN:

68020

Other (OTH)

AF:

0.0695

AC:

147

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

334

668

1003

1337

1671

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

168

252

336

420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0177

Hom.:

Bravo

AF:

0.0486

Asia WGS

AF:

0.106

AC:

368

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

2.6

(source)

DANN

Benign

0.54

PhyloP100

-0.094

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over