Genetic Variant GFAP:p.Asp128His (chr17-44915105-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 8P and 4B. PM1PM5PP3_StrongBS2

The NM_002055.5(GFAP):c.382G>C(p.Asp128His) variant causes a missense change. The variant allele was found at a frequency of 0.0000089 in 1,461,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. D128N) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.01

Publications

0 publications found

Variant links:

Genes affected

GFAP (HGNC:4235): (glial fibrillary acidic protein) This gene encodes one of the major intermediate filament proteins of mature astrocytes. It is used as a marker to distinguish astrocytes from other glial cells during development. Mutations in this gene cause Alexander disease, a rare disorder of astrocytes in the central nervous system. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

GFAP Gene-Disease associations (from GenCC):

Alexander disease
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
Alexander disease type II
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GFAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_002055.5

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-44915105-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 66484.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.948

BS2

High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GFAP	NM_002055.5 link	c.382G>C	p.Asp128His	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2 link	c.382G>C	p.Asp128His	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3 link	c.382G>C	p.Asp128His	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3 link	c.382G>C	p.Asp128His	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.382G>C	p.Asp128His	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461004

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726882

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44686

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26098

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52830

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111918

Other (OTH)

AF:

0.00

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;D;.;.;.;.;D;.;.;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.35

LIST_S2

Benign

0.85

T;T;T;D;T;T;D;D;D;D

M_CAP

Uncertain

0.27

MetaRNN

Pathogenic

0.95

D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Benign

0.0

.;M;.;.;M;M;.;.;.;.

PhyloP100

5.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.0

.;.;D;.;D;.;.;.;.;.

Sift

Pathogenic

0.0

.;.;D;.;D;.;.;.;.;.

Sift4G

Pathogenic

0.0

.;.;D;.;T;.;D;T;.;.

Vest4

0.0

ClinPred

0.99

GERP RS

4.6

PromoterAI

-0.054

Neutral

(source)

Varity_R

0.82

gMVP

0.82

Mutation Taster

=27/73

disease causing

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over