rs60343255

Variant names:

• chr17-44915279-G-A
• rs60343255
• NM_002055.5:c.208C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44915279-G-A
• chr17-44915279-G-T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R70Q) has been classified as Likely 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
• Publications: 6 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 15 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 12 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44915278-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66461.
• 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 VariationId is 66460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.208C>T	p.Arg70Trp	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.208C>T	p.Arg70Trp	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.208C>T	p.Arg70Trp	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.208C>T	p.Arg70Trp	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	c.208C>T	p.Arg70Trp	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

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

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2018

Department of Laboratory Medicine, Soonchunhyang University Seoul Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jul 01, 2019

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.;.
PhyloP100		3.3
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
PromoterAI		-0.0045	Neutral
Varity_R		0.66
gMVP		0.93
Mutation Taster		=62/38	disease causing (ClinVar)

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

Other links and lift over

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