Genetic Variant MPIG6B:p.Ala21Val (chr6-31723639-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_138272.3(MPIG6B):c.62C>T(p.Ala21Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000243 in 1,561,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A21G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

MPIG6B
NM_138272.3 missense, splice_region

Scores

Splicing: ADA: 0.0009184

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.248

Publications

3 publications found

Variant links:

Genes affected

MPIG6B (HGNC:13937): (megakaryocyte and platelet inhibitory receptor G6b) This gene is a member of the immunoglobulin (Ig) superfamily and is located in the major histocompatibility complex (MHC) class III region. The protein encoded by this gene is a glycosylated, plasma membrane-bound cell surface receptor, but soluble isoforms encoded by some transcript variants have been found in the endoplasmic reticulum and Golgi before being secreted. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MPIG6B Gene-Disease associations (from GenCC):

thrombocytopenia, anemia, and myelofibrosis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

MPIG6B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.044110775).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138272.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPIG6B	NM_138272.3	MANE Select	c.62C>T	p.Ala21Val	missense splice_region	Exon 2 of 6	NP_612116.1	O95866-1
MPIG6B	NM_025260.4		c.62C>T	p.Ala21Val	missense splice_region	Exon 2 of 6	NP_079536.2
MPIG6B	NM_138277.3		c.62C>T	p.Ala21Val	missense splice_region	Exon 2 of 5	NP_612121.1	O95866-7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MPIG6B	ENST00000649779.1	MANE Select	c.62C>T	p.Ala21Val	missense splice_region	Exon 2 of 6	ENSP00000497720.1	O95866-1
MPIG6B	ENST00000375809.7	TSL:1	c.62C>T	p.Ala21Val	missense splice_region	Exon 2 of 6	ENSP00000364967.3	O95866-2
MPIG6B	ENST00000375810.8	TSL:1	c.62C>T	p.Ala21Val	missense splice_region	Exon 2 of 5	ENSP00000364968.4	O95866-7

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000144

AC:

AN:

208790

AF XY:

0.0000177

show subpopulations

Gnomad AFR exome

AF:

0.000200

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000135

AC:

AN:

1409164

Hom.:

Cov.:

AF XY:

0.0000115

AC XY:

AN XY:

696616

show subpopulations

African (AFR)

AF:

0.000499

AC:

AN:

32058

American (AMR)

AF:

0.00

AC:

AN:

38440

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23026

East Asian (EAS)

AF:

0.00

AC:

AN:

39280

South Asian (SAS)

AF:

0.00

AC:

AN:

79702

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45466

Middle Eastern (MID)

AF:

0.000550

AC:

AN:

5452

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087590

Other (OTH)

AF:

0.00

AC:

AN:

58150

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000125

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.000410

AC:

AN:

41456

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.000140

ExAC

AF:

0.0000247

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.022

Eigen

Benign

-0.85

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.79

M_CAP

Benign

0.0080

MetaRNN

Benign

0.044

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

PhyloP100

0.25

PROVEAN

Benign

-2.0

REVEL

Benign

0.022

Sift

Benign

0.25

Sift4G

Benign

0.35

Polyphen

0.22

Vest4

0.11

MutPred

0.13

Gain of sheet (P = 0.0149)

MVP

0.076

MPC

0.53

ClinPred

0.039

GERP RS

0.076

PromoterAI

0.012

Neutral

(source)

Varity_R

0.11

gMVP

0.33

Mutation Taster

=69/31

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00092

dbscSNV1_RF

Benign

0.16

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