rs771699440

Variant names:

• chr17-44913423-C-T
• rs771699440
• NM_002055.5:c.626G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM1 BP4_Moderate BS2

The NM_002055.5(GFAP):​c.626G>A​(p.Arg209Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,461,658 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R209W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.34
• Publications: 1 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_002055.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.17313704).
• BS2: High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.626G>A	p.Arg209Gln	missense_variant	Exon 4 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.626G>A	p.Arg209Gln	missense_variant	Exon 4 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.626G>A	p.Arg209Gln	missense_variant	Exon 4 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.626G>A	p.Arg209Gln	missense_variant	Exon 4 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.626G>A	p.Arg209Gln	missense_variant	Exon 4 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250804 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000137 AC: 20 AN: 1461658 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10 AN XY: 727112

African (AFR) AF: 0.00 AC: 0 AN: 33480

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86240

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5676

European-Non Finnish (NFE) AF: 0.0000135 AC: 15 AN: 1111954

Other (OTH) AF: 0.0000166 AC: 1 AN: 60370

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 15, 2018

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.51	.;D;.;.;.;.;.;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;D;T
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.17	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.5	.;L;.;.;L;L;.;.
PhyloP100		1.3
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.2	.;.;N;.;N;.;.;.
REVEL	Benign	0.21
Sift	Benign	0.46	.;.;T;.;T;.;.;.
Sift4G	Benign	0.64	.;.;T;.;T;.;T;.
Polyphen		0.026	.;B;.;.;.;.;.;.
Vest4		0.37, 0.37, 0.38
MutPred		0.50		Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);Loss of helix (P = 0.1706);.;
MVP		0.99
MPC		0.51
ClinPred		0.23	T
GERP RS		-0.82
Varity_R		0.17
gMVP		0.55
Mutation Taster		=69/31	polymorphism

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: rs771699440; hg19: chr17-42990791;