17-44913345-A-G

Variant names:

• chr17-44913345-A-G
• rs60269890
• NM_002055.5:c.704T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The NM_002055.5(GFAP):​c.704T>C​(p.Leu235Pro) 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. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 9.32
• 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.704T>C	p.Leu235Pro	missense_variant	Exon 4 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.704T>C	p.Leu235Pro	missense_variant	Exon 4 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.704T>C	p.Leu235Pro	missense_variant	Exon 4 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.704T>C	p.Leu235Pro	missense_variant	Exon 4 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.704T>C	p.Leu235Pro	missense_variant	Exon 4 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:2

Revision: no classification provided

Submissions by phenotype

not provided Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Alexander disease Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	.;D;.;.;.;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.6	.;H;.;.;H;H;.;.
PhyloP100		9.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-6.5	.;.;D;.;D;.;.;.
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.;.;.
Vest4		0.97, 0.97, 0.99
MutPred		0.97		Gain of disorder (P = 0.0139);Gain of disorder (P = 0.0139);Gain of disorder (P = 0.0139);.;Gain of disorder (P = 0.0139);Gain of disorder (P = 0.0139);Gain of disorder (P = 0.0139);.;
MVP		1.0
MPC		1.6
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.99
gMVP		0.98
Mutation Taster		=0/100	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: rs60269890; hg19: chr17-42990713;