rs267607525

Positions:

• chr17-44913342-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The ENST00000588735.3(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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K236E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP ENST00000588735.3 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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a region_of_interest Coil 2A (size 21) in uniprot entity GFAP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in ENST00000588735.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44913343-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1299244.Status of the report is criteria_provided_single_submitter, 1 stars.

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	P1

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

-

- -

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;.;.
MutationTaster	Benign	1.0	D;N;N;N
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;