Genetic Variant MDGA1:p.Thr921Met (chr6-37638219-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_153487.4(MDGA1):c.2762C>T(p.Thr921Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

MDGA1
NM_153487.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.64

Publications

1 publications found

Variant links:

Genes affected

MDGA1 (HGNC:19267): (MAM domain containing glycosylphosphatidylinositol anchor 1) This gene encodes a glycosylphosphatidylinositol (GPI)-anchored cell surface glycoprotein that is expressed predominantly in the developing nervous system. In addition to possessing several cell adhesion molecule-like domains, the mature protein has six Ig-like domains, a single fibronectin type III domain, a MAM domain and a C-terminal GPI-anchoring site. Studies in other mammals suggest this protein plays a role in cell adhesion, migration, and axon guidance and, in the developing brain, neuronal migration. In humans, this gene is associated with bipolar disorder and schizophrenia. [provided by RefSeq, Oct 2016]

MDGA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0328663).

BP6

Variant 6-37638219-G-A is Benign according to our data. Variant chr6-37638219-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3293795.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153487.4. 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
	MDGA1	NM_153487.4	MANE Select	c.2762C>T	p.Thr921Met	missense	Exon 16 of 17	NP_705691.1	Q8NFP4-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MDGA1	ENST00000434837.8	TSL:1 MANE Select	c.2762C>T	p.Thr921Met	missense	Exon 16 of 17	ENSP00000402584.2	Q8NFP4-1
MDGA1	ENST00000505425.5	TSL:5	c.2762C>T	p.Thr921Met	missense	Exon 16 of 16	ENSP00000422042.1	Q8NFP4-2
MDGA1	ENST00000650466.1		c.2762C>T	p.Thr921Met	missense	Exon 16 of 18	ENSP00000498018.1	A0A3B3IU48

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151668

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000951

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000241

AC:

AN:

249176

AF XY:

0.0000222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000349

AC:

AN:

1461184

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726932

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000333

AC:

AN:

1111442

Other (OTH)

AF:

0.0000497

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

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:

0.0000132

AC:

AN:

151668

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41220

American (AMR)

AF:

0.00

AC:

AN:

15238

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5154

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.0000951

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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.:

ESP6500AA

AF:

0.000251

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000248

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000593

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.062

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.015

LIST_S2

Benign

0.11

M_CAP

Benign

0.019

MetaRNN

Benign

0.033

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.0

PhyloP100

2.6

PrimateAI

Benign

0.43

PROVEAN

Benign

0.39

REVEL

Benign

0.040

Sift

Benign

0.90

Sift4G

Benign

0.23

Polyphen

0.0010

Vest4

0.15

MVP

0.082

MPC

0.28

ClinPred

0.092

GERP RS

3.6

Varity_R

0.020

gMVP

0.25

Mutation Taster

=98/2

polymorphism

(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