chr17-44913342-T-G

Position:

• chr17-44913342-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002055.5(GFAP):​c.707A>C​(p.Lys236Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 3.96

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.707A>C	p.Lys236Thr	missense_variant	4/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.707A>C	p.Lys236Thr	missense_variant	4/10		NP_001350775.1
GFAP	NM_001242376.3	c.707A>C	p.Lys236Thr	missense_variant	4/7		NP_001229305.1
GFAP	NM_001131019.3	c.707A>C	p.Lys236Thr	missense_variant	4/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.707A>C	p.Lys236Thr	missense_variant	4/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	.;D;.;.;.;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.80	T;T;T;T;T;T;T;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.74	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.011	T
MutationAssessor	Benign	0.89	.;L;.;.;L;L;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.2	.;.;D;.;D;.;.;.
REVEL	Uncertain	0.63
Sift	Uncertain	0.0010	.;.;D;.;D;.;.;.
Sift4G	Uncertain	0.0020	.;.;D;.;D;.;D;.
Polyphen		0.084	.;B;.;.;.;.;.;.
Vest4		0.69, 0.67, 0.81
MutPred		0.48		Loss of ubiquitination at K236 (P = 0.0255);Loss of ubiquitination at K236 (P = 0.0255);Loss of ubiquitination at K236 (P = 0.0255);.;Loss of ubiquitination at K236 (P = 0.0255);Loss of ubiquitination at K236 (P = 0.0255);Loss of ubiquitination at K236 (P = 0.0255);.;
MVP		0.98
MPC		0.90
ClinPred		0.98	D
GERP RS		3.9
Varity_R		0.53
gMVP		0.83

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: rs267607525; hg19: chr17-42990710;