chr17-44913334-G-C

Position:

• chr17-44913334-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_002055.5(GFAP):​c.715C>G​(p.Arg239Gly) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:1
• Conservation: PhyloP100: 6.27

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]

GFAP (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.715C>G	p.Arg239Gly	missense_variant	4/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.715C>G	p.Arg239Gly	missense_variant	4/10		NP_001350775.1
GFAP	NM_001242376.3	c.715C>G	p.Arg239Gly	missense_variant	4/7		NP_001229305.1
GFAP	NM_001131019.3	c.715C>G	p.Arg239Gly	missense_variant	4/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.715C>G	p.Arg239Gly	missense_variant	4/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 10, 2017

- -

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	0.93
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	.;H;.;.;H;H;.;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;D;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.97, 0.97, 0.98
MutPred		0.95		Gain of ubiquitination at K236 (P = 0.05);Gain of ubiquitination at K236 (P = 0.05);Gain of ubiquitination at K236 (P = 0.05);.;Gain of ubiquitination at K236 (P = 0.05);Gain of ubiquitination at K236 (P = 0.05);Gain of ubiquitination at K236 (P = 0.05);.;
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.98
gMVP		0.98

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: rs58064122; hg19: chr17-42990702;