dbSNP rs3744470: GFAP:c.*814T>A (chr17-44906533-A-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.*814T>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 0.122 in 152,462 control chromosomes in the GnomAD database, including 1,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.12 ( 1226 hom., cov: 32)

Exomes 𝑓: 0.097 ( 3 hom. )

Consequence

GFAP
NM_002055.5 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.190

Publications

9 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), 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=-0.8).

BP6

Variant 17-44906533-A-T is Benign according to our data. Variant chr17-44906533-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 323601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5 link	c.*814T>A		3_prime_UTR_variant	Exon 9 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2 link	c.*814T>A		3_prime_UTR_variant	Exon 10 of 10		NP_001350775.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 link	c.*814T>A		3_prime_UTR_variant	Exon 9 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes

AF:

0.122

AC:

18583

AN:

151964

Hom.:

1225

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.0296

Gnomad AMR

AF:

0.130

Gnomad ASJ

AF:

0.0519

Gnomad EAS

AF:

0.244

Gnomad SAS

AF:

0.112

Gnomad FIN

AF:

0.168

Gnomad MID

AF:

0.0918

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.125

GnomAD4 exome

AF:

0.0974

AC:

AN:

380

Hom.:

Cov.:

AF XY:

0.0938

AC XY:

AN XY:

192

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.182

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AF:

0.167

AC:

AN:

European-Finnish (FIN)

AF:

0.154

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0909

AC:

AN:

308

Other (OTH)

AF:

0.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

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:

0.122

AC:

18599

AN:

152082

Hom.:

1226

Cov.:

AF XY:

0.125

AC XY:

9283

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.121

AC:

5035

AN:

41470

American (AMR)

AF:

0.130

AC:

1990

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0519

AC:

180

AN:

3470

East Asian (EAS)

AF:

0.244

AC:

1258

AN:

5152

South Asian (SAS)

AF:

0.112

AC:

540

AN:

4826

European-Finnish (FIN)

AF:

0.168

AC:

1775

AN:

10588

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.110

AC:

7502

AN:

67972

Other (OTH)

AF:

0.125

AC:

265

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

803

1605

2408

3210

4013

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

216

432

648

864

1080

<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:

0.0448

Hom.:

Bravo

AF:

0.121

Asia WGS

AF:

0.139

AC:

484

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

1.5

(source)

DANN

Benign

0.57

PhyloP100

0.19

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over