17-44913421-C-A

Variant names:

• chr17-44913421-C-A
• rs57661783
• NM_002055.5:c.628G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_002055.5(GFAP):​c.628G>T​(p.Glu210*) variant causes a stop gained 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GFAP NM_002055.5 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.82
• Publications: 6 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002055.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.628G>T	p.Glu210*	stop_gained	Exon 4 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.628G>T	p.Glu210*	stop_gained	Exon 4 of 10	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.628G>T	p.Glu210*	stop_gained	Exon 4 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.628G>T	p.Glu210*	stop_gained	Exon 4 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.1782G>T		non_coding_transcript_exon	Exon 2 of 5
	GFAP	ENST00000639277.1	TSL:5	c.628G>T	p.Glu210*	stop_gained	Exon 4 of 10	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250898 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		7.8
Vest4		0.93
GERP RS		4.9
Mutation Taster		=7/193	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs57661783; hg19: chr17-42990789;