17-44914081-C-G

Variant names:

• chr17-44914081-C-G
• rs59291670
• NM_002055.5:c.469G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002055.5(GFAP):​c.469G>C​(p.Asp157His) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D157N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.80
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.469G>C	p.Asp157His	missense_variant	Exon 2 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.469G>C	p.Asp157His	missense_variant	Exon 2 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.469G>C	p.Asp157His	missense_variant	Exon 2 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.469G>C	p.Asp157His	missense_variant	Exon 2 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.469G>C	p.Asp157His	missense_variant	Exon 2 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D;.;.;.;.;D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.92	D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Uncertain	2.3	.;M;.;.;M;M;.;.;.;.
PhyloP100		3.8
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	.;.;D;.;D;.;.;.;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	.;.;D;.;D;.;.;.;.;.
Sift4G	Benign	0.074	.;.;T;.;T;.;D;D;.;.
Polyphen		0.31	.;B;.;.;.;.;.;.;.;.
Vest4		0.41, 0.38
MutPred		0.50		Loss of ubiquitination at K154 (P = 0.0413);Loss of ubiquitination at K154 (P = 0.0413);Loss of ubiquitination at K154 (P = 0.0413);.;Loss of ubiquitination at K154 (P = 0.0413);Loss of ubiquitination at K154 (P = 0.0413);Loss of ubiquitination at K154 (P = 0.0413);Loss of ubiquitination at K154 (P = 0.0413);Loss of ubiquitination at K154 (P = 0.0413);.;
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.66
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs59291670; hg19: chr17-42991449;