rs748860341

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr17-44910143-C-G
• chr17-44910143-C-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 4P and 7B. PM2 PM5 BP4_Moderate BP6 BS2

The NM_001363846.2(GFAP):​c.1289G>C​(p.Arg430Pro) 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. 14/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R430H) has been classified as Likely pathogenic.

• 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 U:1 B: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: Likely_benign. The variant received -3 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=0.21266508).
• BP6: Variant 17-44910143-C-G is Benign according to our data. Variant chr17-44910143-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 931895.
• 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>C		intron	N/A	NP_002046.1	P14136-1
	GFAP	NM_001131019.3		c.1289G>C	p.Arg430Pro	missense	Exon 8 of 8	NP_001124491.1	P14136-3
	GFAP	NM_001363846.2		c.1289G>C	p.Arg430Pro	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>C		intron	N/A	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.2797G>C		non_coding_transcript_exon	Exon 5 of 5
	GFAP	ENST00000585543.6	TSL:1	n.324+472G>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000804 AC: 2 AN: 248850 AF XY: 0.0000148

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: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461672 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727120

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

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111838

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

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.094	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Benign	0.96
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.40	T
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.67	T
PhyloP100		1.2
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.24
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.10	T
Vest4		0.12
MutPred		0.26		Gain of glycosylation at R430 (P = 0.0058)
MVP		0.60
ClinPred		0.13	T
GERP RS		3.7
gMVP		0.49

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs748860341; hg19: chr17-42987511;