Genetic Variant NM_001304431.2:c.240C>A (chr5-58494776-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001304431.2(GAPT):c.240C>A(p.His80Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,128 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. H80H) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

GAPT
NM_001304431.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.04

Publications

2 publications found

Variant links:

Genes affected

GAPT (HGNC:26588): (GRB2 binding adaptor protein, transmembrane) Predicted to be involved in B cell homeostasis and B cell proliferation involved in immune response. Located in Golgi apparatus and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

GAPT links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08471024).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001304431.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAPT	NM_001304431.2	MANE Select	c.240C>A	p.His80Gln	missense	Exon 3 of 3	NP_001291360.1	Q8N292
GAPT	NM_001304428.2		c.240C>A	p.His80Gln	missense	Exon 3 of 3	NP_001291357.1	Q8N292
GAPT	NM_001304429.2		c.240C>A	p.His80Gln	missense	Exon 3 of 3	NP_001291358.1	Q8N292

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAPT	ENST00000502276.6	TSL:4 MANE Select	c.240C>A	p.His80Gln	missense	Exon 3 of 3	ENSP00000423113.2	Q8N292
GAPT	ENST00000318469.2	TSL:6	c.240C>A	p.His80Gln	missense	Exon 1 of 1	ENSP00000323075.2	Q8N292
GAPT	ENST00000396776.6	TSL:2	c.240C>A	p.His80Gln	missense	Exon 3 of 3	ENSP00000379997.2	Q8N292

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152128

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74300

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000242

AC:

AN:

41404

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

7.1

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.36

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.065

LIST_S2

Benign

0.24

M_CAP

Benign

0.0073

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

PhyloP100

1.0

PrimateAI

Benign

0.30

PROVEAN

Pathogenic

-4.6

REVEL

Benign

0.035

Sift

Benign

0.13

Sift4G

Benign

0.48

Polyphen

0.24

Vest4

0.14

MutPred

0.26

Loss of methylation at R85 (P = 0.089)

MVP

0.088

MPC

0.46

ClinPred

0.25

GERP RS

0.97

Varity_R

0.16

gMVP

0.16

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over