rs60095124

chr17-44915300-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 5 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, 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/exons	MANE	UniProt
GFAP	NM_002055.5	c.187A>C	p.Lys63Gln	missense_variant	1/9	ENST00000588735.3
GFAP	NM_001363846.2	c.187A>C	p.Lys63Gln	missense_variant	1/10
GFAP	NM_001242376.3	c.187A>C	p.Lys63Gln	missense_variant	1/7
GFAP	NM_001131019.3	c.187A>C	p.Lys63Gln	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.187A>C	p.Lys63Gln	missense_variant	1/9	1	NM_002055.5	P1

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

not provided, no classification provided

literature only

Epithelial Biology; Institute of Medical Biology, Singapore

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- -

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

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
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
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.62	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
Varity_R		0.81
gMVP		0.88

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: rs60095124; hg19: chr17-42992668;