17-44915279-G-A

Position:

• chr17-44915279-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):​c.208C>T​(p.Arg70Trp) variant causes a missense change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3 O:2
• Conservation: PhyloP100: 3.27

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 17-44915279-G-A is Pathogenic according to our data. Variant chr17-44915279-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 66460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.208C>T	p.Arg70Trp	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.208C>T	p.Arg70Trp	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.208C>T	p.Arg70Trp	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.208C>T	p.Arg70Trp	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.208C>T	p.Arg70Trp	missense_variant	1/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Alexander disease Pathogenic:2 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Laboratory Medicine, Soonchunhyang University Seoul Hospital	Aug 10, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2019	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.;D;.;.;.
Eigen	Benign	0.18
Eigen_PC	Benign	0.082
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Uncertain	2.4	.;M;.;M;M;.;.;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.5	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;D;.;D;D;.;.
Polyphen		0.98	.;D;.;.;.;.;.;.;.
Vest4		0.65, 0.70, 0.83
MutPred		0.94		Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);Gain of catalytic residue at M73 (P = 0.0054);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		1.6
Varity_R		0.66
gMVP		0.93

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: rs60343255; hg19: chr17-42992647; COSMIC: COSV53653176; COSMIC: COSV53653176;