17-44910144-G-T

Variant names:

• chr17-44910144-G-T
• rs78994946
• NM_002055.5:c.1171+471C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM2 PM5 BP4_Moderate BP6_Moderate

The NM_001363846.2(GFAP):​c.1288C>A​(p.Arg430Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R430P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: GFAP NM_001363846.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.96
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-44910143-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190367.
• BP4: Computational evidence support a benign effect (MetaRNN=0.21261773).
• BP6: Variant 17-44910144-G-T is Benign according to our data. Variant chr17-44910144-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1962658.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363846.2. 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.1171+471C>A		intron	N/A	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.1288C>A	p.Arg430Ser	missense	Exon 8 of 10	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001131019.3		c.1288C>A	p.Arg430Ser	missense	Exon 8 of 8	NP_001124491.1	P14136-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.1171+471C>A		intron	N/A	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.2796C>A		non_coding_transcript_exon	Exon 5 of 5
	GFAP	ENST00000585543.6	TSL:1	n.324+471C>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	21
DANN	Benign	0.97
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.39	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.76	T
PhyloP100		3.0
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.26
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.14	T
Vest4		0.14
MutPred		0.25		Gain of glycosylation at R430 (P = 0.0018)
MVP		0.57
ClinPred		0.39	T
GERP RS		3.8
gMVP		0.51

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: rs78994946; hg19: chr17-42987512;