17-44905825-A-G

Variant names:

• chr17-44905825-A-G
• rs17027
• NM_002055.5:c.*1522T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002055.5(GFAP):​c.*1522T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.261 in 152,368 control chromosomes in the GnomAD database, including 5,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5279 hom., cov: 32)
  • Exomes 𝑓: 0.26 (13 hom.)
• Consequence: GFAP NM_002055.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.394
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 17-44905825-A-G is Benign according to our data. Variant chr17-44905825-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 323596.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

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.*1522T>C		3_prime_UTR	Exon 9 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.*1522T>C		3_prime_UTR	Exon 10 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.*1522T>C		3_prime_UTR	Exon 9 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000253408.11	TSL:5	c.*1522T>C		3_prime_UTR	Exon 10 of 10	ENSP00000253408.5	A0A1X7SBR3
	GFAP	ENST00000867443.1		c.*1522T>C		3_prime_UTR	Exon 9 of 9	ENSP00000537502.1

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39721 AN: 151938 Hom.: 5274 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.219

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.241

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.265

GnomAD4 exome AF: 0.260 AC: 81 AN: 312 Hom.: 13 Cov.: 0 AF XY: 0.286 AC XY: 60 AN XY: 210

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AF: 0.500 AC: 7 AN: 14

European-Finnish (FIN) AF: 0.500 AC: 3 AN: 6

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.248 AC: 68 AN: 274

Other (OTH) AF: 0.300 AC: 3 AN: 10

GnomAD4 genome AF: 0.261 AC: 39748 AN: 152056 Hom.: 5279 Cov.: 32 AF XY: 0.261 AC XY: 19390 AN XY: 74304

African (AFR) AF: 0.232 AC: 9610 AN: 41474

American (AMR) AF: 0.226 AC: 3459 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 834 AN: 3466

East Asian (EAS) AF: 0.252 AC: 1303 AN: 5176

South Asian (SAS) AF: 0.272 AC: 1307 AN: 4812

European-Finnish (FIN) AF: 0.318 AC: 3361 AN: 10562

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.280 AC: 19044 AN: 67972

Other (OTH) AF: 0.263 AC: 554 AN: 2110

Alfa AF: 0.279 Hom.: 1233

Bravo AF: 0.253

Asia WGS AF: 0.228 AC: 791 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.82
DANN	Benign	0.48
PhyloP100		-0.39
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: rs17027; hg19: chr17-42983193;