rs797044590

Positions:

• chr17-44910632-G-A
• chr17-44910632-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_002055.5(GFAP):​c.1154C>T​(p.Ser385Phe) 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 not provided (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.34

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a modified_residue Phosphoserine (size 0) in uniprot entity GFAP_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.846

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1154C>T	p.Ser385Phe	missense_variant	7/9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1154C>T	p.Ser385Phe	missense_variant	7/10		NP_001350775.1
GFAP	NM_001242376.3	c.1154C>T	p.Ser385Phe	missense_variant	7/7		NP_001229305.1
GFAP	NM_001131019.3	c.1154C>T	p.Ser385Phe	missense_variant	7/8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1154C>T	p.Ser385Phe	missense_variant	7/9	1	NM_002055.5	ENSP00000466598	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1432106 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 709080

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Alexander disease Other:1

not provided, no classification provided

literature only

GeneReviews

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.71	.;D;.;.;.;.;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T;D
M_CAP	Uncertain	0.22	D
MetaRNN	Pathogenic	0.85	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Pathogenic	2.9	.;M;.;.;.;M;M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	.;.;D;.;.;D;.;.
REVEL	Pathogenic	0.75
Sift	Uncertain	0.0030	.;.;D;.;.;D;.;.
Sift4G	Uncertain	0.0030	.;.;D;.;.;D;.;D
Polyphen		0.14	.;B;.;.;.;.;.;.
Vest4		0.82, 0.82
MutPred		0.52		Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);.;.;Loss of disorder (P = 0.0409);Loss of disorder (P = 0.0409);.;
MVP		1.0
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.63
gMVP		0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044590; hg19: chr17-42988000;