rs17629022

Variant names:

• chr17-44914681-T-C
• rs17629022
• ENST00000591327.2:n.819A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000591327.2(GFAP):​n.819A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.208 in 330,546 control chromosomes in the GnomAD database, including 7,648 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.21 (3468 hom., cov: 32)
  • Exomes 𝑓: 0.20 (4180 hom.)
• Consequence: GFAP ENST00000591327.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.58
• Publications: 10 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.226 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000591327.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.461+345A>G		intron	N/A	NP_002046.1
	GFAP	NM_001363846.2		c.461+345A>G		intron	N/A	NP_001350775.1
	GFAP	NM_001242376.3		c.461+345A>G		intron	N/A	NP_001229305.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000591327.2	TSL:1	n.819A>G		non_coding_transcript_exon	Exon 1 of 5
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.461+345A>G		intron	N/A	ENSP00000466598.2
	GFAP	ENST00000586127.6	TSL:5	n.398A>G		non_coding_transcript_exon	Exon 1 of 6

Frequencies

GnomAD3 genomes AF: 0.211 AC: 32033 AN: 152012 Hom.: 3464 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.192

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.243

Gnomad EAS AF: 0.0864

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.196

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.218

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.205 AC: 36542 AN: 178416 Hom.: 4180 Cov.: 0 AF XY: 0.207 AC XY: 19342 AN XY: 93566

African (AFR) AF: 0.220 AC: 1217 AN: 5520

American (AMR) AF: 0.145 AC: 924 AN: 6354

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 1242 AN: 5244

East Asian (EAS) AF: 0.0950 AC: 892 AN: 9394

South Asian (SAS) AF: 0.231 AC: 4998 AN: 21600

European-Finnish (FIN) AF: 0.194 AC: 2024 AN: 10452

Middle Eastern (MID) AF: 0.329 AC: 239 AN: 726

European-Non Finnish (NFE) AF: 0.211 AC: 22918 AN: 108800

Other (OTH) AF: 0.202 AC: 2088 AN: 10326

GnomAD4 genome AF: 0.211 AC: 32054 AN: 152130 Hom.: 3468 Cov.: 32 AF XY: 0.208 AC XY: 15439 AN XY: 74378

African (AFR) AF: 0.230 AC: 9553 AN: 41498

American (AMR) AF: 0.161 AC: 2459 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.243 AC: 843 AN: 3470

East Asian (EAS) AF: 0.0864 AC: 447 AN: 5172

South Asian (SAS) AF: 0.231 AC: 1115 AN: 4822

European-Finnish (FIN) AF: 0.196 AC: 2073 AN: 10596

Middle Eastern (MID) AF: 0.344 AC: 101 AN: 294

European-Non Finnish (NFE) AF: 0.218 AC: 14831 AN: 67966

Other (OTH) AF: 0.217 AC: 457 AN: 2106

Alfa AF: 0.214 Hom.: 2734

Bravo AF: 0.207

Asia WGS AF: 0.176 AC: 611 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.40
DANN	Benign	0.65
PhyloP100		-2.6
PromoterAI		-0.0025	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs17629022; hg19: chr17-42992049;