rs60095124

Variant names:

• chr17-44915300-T-G
• rs60095124
• NM_002055.5:c.187A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002055.5(GFAP):​c.187A>C​(p.Lys63Gln) variant causes a missense change involving the alteration of a non-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: 1.15
• 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: 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 5 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.187A>C	p.Lys63Gln	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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	Benign	0.18
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Uncertain	0.97
DEOGEN2	Uncertain	0.46	.;T;.;.;.;T;.;.;.
Eigen	Benign	-0.39
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.073	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.59	T
MutationAssessor	Uncertain	2.6	.;M;.;M;M;.;.;.;.
PhyloP100		1.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.5	.;.;N;N;.;.;.;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.023	.;.;D;D;.;.;.;.;.
Sift4G	Benign	0.15	.;.;T;T;.;T;T;.;.
Polyphen		0.37	.;B;.;.;.;.;.;.;.
Vest4		0.61, 0.64, 0.75
MutPred		0.83		Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);Loss of ubiquitination at K63 (P = 0.0051);
MVP		0.96
MPC		0.98
ClinPred		0.88	D
GERP RS		3.7
PromoterAI		-0.020	Neutral
Varity_R		0.81
gMVP		0.88
Mutation Taster		=15/85	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: rs60095124; hg19: chr17-42992668;