17-44911371-A-G

Position:

• chr17-44911371-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The ENST00000588735.3(GFAP):​c.992T>C​(p.Leu331Pro) variant causes a missense change involving the alteration of a 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). Synonymous variant affecting the same amino acid position (i.e. L331L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP ENST00000588735.3 missense
• Clinical Significance: not provided no classification provided O:2
• Conservation: PhyloP100: 9.32

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 8 ACMG points.

• PM1: In a region_of_interest Coil 2B (size 120) in uniprot entity GFAP_HUMAN there are 28 pathogenic changes around while only 6 benign (82%) in ENST00000588735.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.992T>C	p.Leu331Pro	missense_variant	6/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.992T>C	p.Leu331Pro	missense_variant	6/10		NP_001350775.1
GFAP	NM_001242376.3	c.992T>C	p.Leu331Pro	missense_variant	6/7		NP_001229305.1
GFAP	NM_001131019.3	c.992T>C	p.Leu331Pro	missense_variant	6/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.992T>C	p.Leu331Pro	missense_variant	6/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

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

-

- -

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;.
Eigen	Pathogenic	0.76
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;T;T;T;T;T
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	.;H;.;.;H;H
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.2	.;.;D;.;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0020	.;.;D;.;D;.
Sift4G	Pathogenic	0.0	.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.94, 0.94
MutPred		0.95		Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);.;Loss of stability (P = 0.0143);Loss of stability (P = 0.0143);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.4
Varity_R		0.99
gMVP		1.0

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: rs59985777; hg19: chr17-42988739;