rs61622935

Positions:

• chr17-44915225-G-A
• chr17-44915225-G-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_002055.5(GFAP):​c.262C>T​(p.Arg88Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 152,344 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8 O:2
• Conservation: PhyloP100: 9.78

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 Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 17-44915225-G-A is Pathogenic according to our data. Variant chr17-44915225-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 16172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915225-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.262C>T	p.Arg88Cys	missense_variant	1/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.262C>T	p.Arg88Cys	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3	c.262C>T	p.Arg88Cys	missense_variant	1/7		NP_001229305.1
GFAP	NM_001131019.3	c.262C>T	p.Arg88Cys	missense_variant	1/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.262C>T	p.Arg88Cys	missense_variant	1/9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152226 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000656 AC: 1 AN: 152344 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74504

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 20, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17629821, 16505300, 34865968, 36088400, 17318298, 11567214, 26478912, 15477559, 15732097, 12034785, 18079314, 16217707, 17894839, 34146839, 35831840, 31069529, 36601294) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2022	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 16172). This missense change has been observed in individual(s) with Alexander disease (PMID: 11567214, 15732097, 26478912). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 88 of the GFAP protein (p.Arg88Cys). -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	GFAP: PM6:Strong, PM1, PM2, PM5, PS4:Moderate, PP4, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 30, 2019	Not found in the total gnomAD dataset, and the data is high quality. Predicted to have a damaging effect on the protein. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. 10 de novo cases with parental identity not confirmed. -

Alexander disease Pathogenic:4 Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000016172, PS1_S). Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 17318298, PS3_S). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.942, 3CNET: 0.966, PP3_P). A missense variant is a common mechanism associated with Alexander disease (PP2_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). The variant is located in a well-established functional domain or exonic hotspot, where pathogenic variants have frequently reported (PM1_M). A different missense change at the same codon has been reported to be associated with GFAP related disorder (ClinVar ID: VCV000016173, PM5_P).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Oct 28, 2022	ACMG classification criteria: PS1 strong, PS3 supporting, PS4 strong, PM2 moderated, PM6 moderated, PP3 supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.73
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	.;D;.;.;.;D;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	.;H;.;H;H;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-6.8	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;.;D;D;.;D;D;.;.
Polyphen		1.0	.;D;.;.;.;.;.;.;.
Vest4		0.95, 0.96
MutPred		0.95		Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);Loss of MoRF binding (P = 0.0054);
MVP		1.0
MPC		1.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.83
gMVP		0.95

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: rs61622935; hg19: chr17-42992593; COSMIC: COSV53650717; COSMIC: COSV53650717;