rs267607517

Variant names:

• chr17-44910638-G-A
• rs267607517
• NM_002055.5:c.1148C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44910638-G-A
• chr17-44910638-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_002055.5(GFAP):​c.1148C>T​(p.Thr383Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 O:2
• Conservation: PhyloP100: 2.27

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a modified_residue Phosphothreonine (size 0) in uniprot entity GFAP_HUMAN
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1148C>T	p.Thr383Ile	missense_variant	Exon 7 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1148C>T	p.Thr383Ile	missense_variant	Exon 7 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.1148C>T	p.Thr383Ile	missense_variant	Exon 7 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.1148C>T	p.Thr383Ile	missense_variant	Exon 7 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1148C>T	p.Thr383Ile	missense_variant	Exon 7 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 383 of the GFAP protein (p.Thr383Ile). This variant is not present in population databases (gnomAD no frequency). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 66447). This missense change has been observed in individuals with Alexander disease (PMID: 21165639; Invitae). -

Alexander disease Other:1

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D;.;.;.;.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D;D;T;D;D;D;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Uncertain	2.2	.;M;.;.;.;M;M;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	.;.;D;.;.;D;.;.
REVEL	Uncertain	0.56
Sift	Uncertain	0.0090	.;.;D;.;.;D;.;.
Sift4G	Uncertain	0.013	.;.;D;.;.;D;.;D
Polyphen		0.93	.;P;.;.;.;.;.;.
Vest4		0.56, 0.56
MutPred		0.45		Loss of disorder (P = 0.148);Loss of disorder (P = 0.148);Loss of disorder (P = 0.148);.;.;Loss of disorder (P = 0.148);Loss of disorder (P = 0.148);.;
MVP		1.0
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.30
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs267607517; hg19: chr17-42988006;