chr17-44911266-T-C

Variant names:

• chr17-44911266-T-C
• rs267607502
• NM_002055.5:c.1097A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_001363846.2(GFAP):​c.1097A>G​(p.Tyr366Cys) 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. 13/22 in silico tools predict a damaging 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. Y366H) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_001363846.2 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 8.02
• Publications: 2 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 10 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_001363846.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44911267-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 66434.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363846.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.1097A>G	p.Tyr366Cys	missense	Exon 6 of 9	NP_002046.1
	GFAP	NM_001363846.2		c.1097A>G	p.Tyr366Cys	missense	Exon 6 of 10	NP_001350775.1
	GFAP	NM_001242376.3		c.1097A>G	p.Tyr366Cys	missense	Exon 6 of 7	NP_001229305.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.1097A>G	p.Tyr366Cys	missense	Exon 6 of 9	ENSP00000466598.2
	GFAP	ENST00000585543.6	TSL:1	n.250A>G		non_coding_transcript_exon	Exon 1 of 4
	GFAP	ENST00000591327.2	TSL:1	n.2251A>G		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Alexander disease (1)
-	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.2	H
PhyloP100		8.0
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-8.1	D
REVEL	Pathogenic	0.98
Sift	Uncertain	0.0030	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.93		Loss of ubiquitination at K368 (P = 0.0777)
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.3
PromoterAI		-0.15	Neutral
Varity_R		0.94
gMVP		1.0
Mutation Taster		=7/93	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: rs267607502; hg19: chr17-42988634;