rs57815192

Positions:

• chr17-44911251-T-A
• chr17-44911251-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The ENST00000588735.3(GFAP):​c.1112A>T​(p.Glu371Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E371G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP ENST00000588735.3 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 8.02

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in ENST00000588735.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44911252-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1199219.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.985

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1112A>T	p.Glu371Val	missense_variant	6/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1112A>T	p.Glu371Val	missense_variant	6/10		NP_001350775.1
GFAP	NM_001242376.3	c.1112A>T	p.Glu371Val	missense_variant	6/7		NP_001229305.1
GFAP	NM_001131019.3	c.1112A>T	p.Glu371Val	missense_variant	6/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1112A>T	p.Glu371Val	missense_variant	6/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

-

- -

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.;.;D;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	.;H;.;.;.;H;H;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-6.2	.;.;D;.;.;D;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	.;.;D;.;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.92, 0.92
MutPred		0.90		Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);.;.;Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);.;.;
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.97
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs57815192; hg19: chr17-42988619;