17-44914095-TG-TGG

Variant names:

• chr17-44914095-T-TG
• rs572562362
• NM_002055.5:c.462-8dupC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002055.5(GFAP):​c.462-8dupC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00101 in 1,548,474 control chromosomes in the GnomAD database, including 12 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (7 hom., cov: 32)
  • Exomes 𝑓: 0.00050 (5 hom.)
• Consequence: GFAP NM_002055.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:6
• Conservation: PhyloP100: -0.246
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 17-44914095-T-TG is Benign according to our data. Variant chr17-44914095-T-TG is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 323620.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00576 (869/150764) while in subpopulation AFR AF = 0.0206 (844/40956). AF 95% confidence interval is 0.0195. There are 7 homozygotes in GnomAd4. There are 410 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 869 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002055.5. 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.462-8dupC		splice_region intron	N/A	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.462-8dupC		splice_region intron	N/A	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.462-8dupC		splice_region intron	N/A	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.462-8dupC		splice_region intron	N/A	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.1404dupC		non_coding_transcript_exon	Exon 1 of 5
	GFAP	ENST00000588037.1	TSL:3	c.475dupC	p.His159ProfsTer7	frameshift	Exon 2 of 3	ENSP00000466163.1	K7ELP4

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 864 AN: 150658 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000991

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0000443

Gnomad OTH AF: 0.00290

GnomAD2 exomes AF: 0.00107 AC: 169 AN: 158326 AF XY: 0.000744

Gnomad AFR exome AF: 0.0169

Gnomad AMR exome AF: 0.000645

Gnomad ASJ exome AF: 0.00

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: 0.000500 AC: 699 AN: 1397710 Hom.: 5 Cov.: 30 AF XY: 0.000444 AC XY: 306 AN XY: 689804

African (AFR) AF: 0.0187 AC: 592 AN: 31624

American (AMR) AF: 0.000781 AC: 28 AN: 35832

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25160

East Asian (EAS) AF: 0.00 AC: 0 AN: 35958

South Asian (SAS) AF: 0.0000757 AC: 6 AN: 79274

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5620

European-Non Finnish (NFE) AF: 0.00000557 AC: 6 AN: 1076900

Other (OTH) AF: 0.00116 AC: 67 AN: 57966

GnomAD4 genome AF: 0.00576 AC: 869 AN: 150764 Hom.: 7 Cov.: 32 AF XY: 0.00557 AC XY: 410 AN XY: 73556

African (AFR) AF: 0.0206 AC: 844 AN: 40956

American (AMR) AF: 0.000990 AC: 15 AN: 15154

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4748

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10394

Middle Eastern (MID) AF: 0.00347 AC: 1 AN: 288

European-Non Finnish (NFE) AF: 0.0000443 AC: 3 AN: 67670

Other (OTH) AF: 0.00287 AC: 6 AN: 2092

Alfa AF: 0.00269 Hom.: 1

Bravo AF: 0.00653

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	2	Alexander disease (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.25
Mutation Taster		=100/0	polymorphism

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: rs572562362; hg19: chr17-42991463;