17-44913756-A-G

Position:

• chr17-44913756-A-G

Variant summary

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

The ENST00000588735.3(GFAP):​c.590T>C​(p.Ile197Thr) 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. 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. I197N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP ENST00000588735.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.32

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 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, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.590T>C	p.Ile197Thr	missense_variant	3/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.590T>C	p.Ile197Thr	missense_variant	3/10		NP_001350775.1
GFAP	NM_001242376.3	c.590T>C	p.Ile197Thr	missense_variant	3/7		NP_001229305.1
GFAP	NM_001131019.3	c.590T>C	p.Ile197Thr	missense_variant	3/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.590T>C	p.Ile197Thr	missense_variant	3/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	.;D;.;.;.;.;D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Pathogenic	3.3	.;M;.;.;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-4.5	.;.;D;.;D;.;.;.
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.
Sift4G	Pathogenic	0.0010	.;.;D;.;D;.;D;D
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.90, 0.89, 0.88
MutPred		0.81		Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);.;Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);Loss of stability (P = 0.0235);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.96
gMVP		0.63

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: rs779356682; hg19: chr17-42991124;