17-44910143-C-T

Variant names:

• chr17-44910143-C-T
• rs748860341
• NM_002055.5:c.1171+472G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 7P and 4B. PS3 PM2 PP5 BS2

The NM_001363846.2(GFAP):​c.1289G>A​(p.Arg430His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV004229676: Assessment of experimental evidence suggests this variant results in abnormal RNA splicing and protein function (PMID:23634874, 32126152).". 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)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: GFAP NM_001363846.2 missense, splice_region
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 O:1
• Conservation: PhyloP100: 1.25
• Publications: 8 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 3 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV004229676: Assessment of experimental evidence suggests this variant results in abnormal RNA splicing and protein function (PMID: 23634874, 32126152).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-44910143-C-T is Pathogenic according to our data. Variant chr17-44910143-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190367.
• BS2: High AC in GnomAdExome4 at 5 AD gene.

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+472G>A		intron	N/A	NP_002046.1	P14136-1
	GFAP	NM_001131019.3		c.1289G>A	p.Arg430His	missense	Exon 8 of 8	NP_001124491.1	P14136-3
	GFAP	NM_001363846.2		c.1289G>A	p.Arg430His	missense splice_region	Exon 8 of 10	NP_001350775.1	A0A1X7SBR3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.1171+472G>A		intron	N/A	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.2797G>A		non_coding_transcript_exon	Exon 5 of 5
	GFAP	ENST00000585543.6	TSL:1	n.324+472G>A		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248850 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000996

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461672 Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727120

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111838

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000177 Hom.: 0

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	not provided (2)
-	-	-	Alexander disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.0045	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.51	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.66	T
PhyloP100		1.2
PROVEAN	Benign	1.5	N
REVEL	Uncertain	0.62
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.10	T
Vest4		0.11
MutPred		0.23		Loss of methylation at R430 (P = 0.0939)
MVP		0.80
ClinPred		0.63	D
GERP RS		3.7
gMVP		0.39
Mutation Taster		=25/75	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.39		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs748860341; hg19: chr17-42987511;