chr17-44913733-C-G

Variant names:

• chr17-44913733-C-G
• rs267607507
• NM_002055.5:c.613G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_002055.5(GFAP):​c.613G>C​(p.Glu205Gln) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E205K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.04
• Publications: 4 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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 chr17-44913733-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 66488.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.613G>C	p.Glu205Gln	missense	Exon 3 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.613G>C	p.Glu205Gln	missense	Exon 3 of 10	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.613G>C	p.Glu205Gln	missense	Exon 3 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.613G>C	p.Glu205Gln	missense	Exon 3 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.1767G>C		non_coding_transcript_exon	Exon 1 of 5
	GFAP	ENST00000639277.1	TSL:5	c.613G>C	p.Glu205Gln	missense	Exon 3 of 10	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Uncertain	0.64	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.0
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-2.4	N
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.051	T
Polyphen		0.92	P
Vest4		0.45
MutPred		0.68		Gain of MoRF binding (P = 0.0552)
MVP		0.99
MPC		1.1
ClinPred		0.94	D
GERP RS		3.7
Varity_R		0.75
gMVP		0.60

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: rs267607507; hg19: chr17-42991101; COSMIC: COSV99493614; COSMIC: COSV99493614;