Genetic Variant GFAP:c.*1001G>A (chr17-44906346-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002055.5(GFAP):c.*1001G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.108 in 152,590 control chromosomes in the GnomAD database, including 890 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.11 ( 888 hom., cov: 32)

Exomes 𝑓: 0.12 ( 2 hom. )

Consequence

GFAP
NM_002055.5 3_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.873

Publications

15 publications found

Variant links:

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

GFAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 17-44906346-C-T is Benign according to our data. Variant chr17-44906346-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 369152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.113 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.*1001G>A		3_prime_UTR	Exon 9 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.*1001G>A		3_prime_UTR	Exon 10 of 10	NP_001350775.1	A0A1X7SBR3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GFAP	ENST00000588735.3	TSL:1 MANE Select	c.*1001G>A	3_prime_UTR	Exon 9 of 9	ENSP00000466598.2	P14136-1
GFAP	ENST00000253408.11	TSL:5	c.*1001G>A	3_prime_UTR	Exon 10 of 10	ENSP00000253408.5	A0A1X7SBR3
GFAP	ENST00000867443.1		c.*1001G>A	3_prime_UTR	Exon 9 of 9	ENSP00000537502.1

Frequencies

GnomAD3 genomes

AF:

0.108

AC:

16371

AN:

152026

Hom.:

890

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0952

Gnomad AMI

AF:

0.110

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.0906

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0853

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.116

Gnomad OTH

AF:

0.131

GnomAD4 exome

AF:

0.121

AC:

AN:

446

Hom.:

Cov.:

AF XY:

0.118

AC XY:

AN XY:

288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.00

AC:

AN:

European-Finnish (FIN)

AF:

0.0658

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

AN:

European-Non Finnish (NFE)

AF:

0.135

AC:

AN:

312

Other (OTH)

AF:

0.118

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.524

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.108

AC:

16371

AN:

152144

Hom.:

888

Cov.:

AF XY:

0.106

AC XY:

7852

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.0951

AC:

3943

AN:

41470

American (AMR)

AF:

0.105

AC:

1602

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

593

AN:

3472

East Asian (EAS)

AF:

0.0906

AC:

469

AN:

5178

South Asian (SAS)

AF:

0.115

AC:

556

AN:

4824

European-Finnish (FIN)

AF:

0.0853

AC:

905

AN:

10608

Middle Eastern (MID)

AF:

0.255

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.116

AC:

7853

AN:

67978

Other (OTH)

AF:

0.130

AC:

275

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

758

1516

2274

3032

3790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

176

352

528

704

880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.112

Hom.:

456

Bravo

AF:

0.109

Asia WGS

AF:

0.103

AC:

357

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Primary ciliary dyskinesia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

8.5

(source)

DANN

Benign

0.52

PhyloP100

0.87

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over