17-44915269-A-G

Variant names:

• chr17-44915269-A-G
• rs61060395
• NM_002055.5:c.218T>C

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_002055.5(GFAP):​c.218T>C​(p.Met73Thr) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M73R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 9.32
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• Alexander disease

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44915268-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2132009.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 17-44915269-A-G is Pathogenic according to our data. Variant chr17-44915269-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 190334.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.218T>C	p.Met73Thr	missense_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.218T>C	p.Met73Thr	missense_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.218T>C	p.Met73Thr	missense_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.218T>C	p.Met73Thr	missense_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.218T>C	p.Met73Thr	missense_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alexander disease Pathogenic:1 Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D;.;.;.;D;.;.;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Pathogenic	4.0	.;H;.;H;H;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.6	.;.;D;D;.;.;.;.;.
REVEL	Pathogenic	0.88
Sift	Pathogenic	0.0	.;.;D;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;.;D;D;.;D;D;.;.
Polyphen		0.14	.;B;.;.;.;.;.;.;.
Vest4		0.80, 0.81, 0.81
MutPred		0.94		Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);Gain of phosphorylation at M73 (P = 0.0357);
MVP		1.0
MPC		0.78
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		0.016	Neutral
Varity_R		0.96
gMVP		0.98
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs61060395; hg19: chr17-42992637;