17-44911374-C-G

Variant names:

• chr17-44911374-C-G
• rs983143417
• NM_002055.5:c.989G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_002055.5(GFAP):​c.989G>C​(p.Arg330Pro) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R330G) has been classified 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
• Conservation: PhyloP100: 5.03
• Publications: 1 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a region_of_interest Coil 2B (size 120) in uniprot entity GFAP_HUMAN there are 25 pathogenic changes around while only 5 benign (83%) in NM_002055.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.989G>C	p.Arg330Pro	missense_variant	Exon 6 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.989G>C	p.Arg330Pro	missense_variant	Exon 6 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.989G>C	p.Arg330Pro	missense_variant	Exon 6 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.989G>C	p.Arg330Pro	missense_variant	Exon 6 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.989G>C	p.Arg330Pro	missense_variant	Exon 6 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Alexander disease Uncertain:1

Apr 04, 2016

Undiagnosed Diseases Network, NIH

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This VUS was found in a 34-year-old female with retinitis pigmentosa (thought to be unrelated to this finding), left-sided hemidystonia, hemiplegia, truncal and axial dystonia, left-sided muscle atrophy, brain tumors, constipation and functional megacolon, macrocephaly, poor dentition, mild scoliosis, hyperpigmented macules on forearms and seborrhea of the scalp. This individual has been reported in PMID: 30046660. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;D;.;.;.;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.81	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.9	.;M;.;.;M;M
PhyloP100		5.0
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-5.1	.;.;D;.;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0010	.;.;D;.;D;.
Sift4G	Uncertain	0.012	.;.;D;.;D;.
Polyphen		1.0	.;D;.;.;.;.
Vest4		0.79, 0.80
MutPred		0.66		Gain of glycosylation at R330 (P = 0.0364);Gain of glycosylation at R330 (P = 0.0364);Gain of glycosylation at R330 (P = 0.0364);.;Gain of glycosylation at R330 (P = 0.0364);Gain of glycosylation at R330 (P = 0.0364);
MVP		1.0
ClinPred		1.0	D
GERP RS		3.5
PromoterAI		0.0044	Neutral
Varity_R		0.97
gMVP		0.99

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

Other links and lift over

dbSNP: rs983143417; hg19: chr17-42988742;