dbSNP rs2229011: GFAP:p.Pro47Pro (chr17-44915346-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002055.5(GFAP):c.141G>A(p.Pro47Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0436 in 1,612,616 control chromosomes in the GnomAD database, including 1,770 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.036 ( 146 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1624 hom. )

Consequence

GFAP
NM_002055.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -2.59

Publications

6 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: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Genomics England PanelApp
Alexander disease type II
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

GFAP links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_002055.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 17-44915346-C-T is Benign according to our data. Variant chr17-44915346-C-T is described in ClinVar as Benign. ClinVar VariationId is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.59 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0361 (5494/152292) while in subpopulation NFE AF = 0.0487 (3313/68008). AF 95% confidence interval is 0.0473. There are 146 homozygotes in GnomAd4. There are 2754 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 5494 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFAP	NM_002055.5	MANE Select	c.141G>A	p.Pro47Pro	synonymous	Exon 1 of 9	NP_002046.1	P14136-1
GFAP	NM_001363846.2		c.141G>A	p.Pro47Pro	synonymous	Exon 1 of 10	NP_001350775.1	A0A1X7SBR3
GFAP	NM_001242376.3		c.141G>A	p.Pro47Pro	synonymous	Exon 1 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GFAP	ENST00000588735.3	TSL:1 MANE Select	c.141G>A	p.Pro47Pro	synonymous	Exon 1 of 9	ENSP00000466598.2	P14136-1
GFAP	ENST00000591327.2	TSL:1	n.154G>A		non_coding_transcript_exon	Exon 1 of 5
GFAP	ENST00000639277.1	TSL:5	c.141G>A	p.Pro47Pro	synonymous	Exon 1 of 10	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes

AF:

0.0361

AC:

5492

AN:

152174

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00912

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0388

Gnomad ASJ

AF:

0.0701

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0740

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0487

Gnomad OTH

AF:

0.0306

GnomAD2 exomes

AF:

0.0386

AC:

9644

AN:

249756

AF XY:

0.0396

show subpopulations

Gnomad AFR exome

AF:

0.00745

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0730

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0698

Gnomad NFE exome

AF:

0.0509

Gnomad OTH exome

AF:

0.0434

GnomAD4 exome

AF:

0.0444

AC:

64794

AN:

1460324

Hom.:

1624

Cov.:

AF XY:

0.0439

AC XY:

31846

AN XY:

726206

show subpopulations

African (AFR)

AF:

0.00705

AC:

236

AN:

33468

American (AMR)

AF:

0.0258

AC:

1151

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.0730

AC:

1908

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39668

South Asian (SAS)

AF:

0.0144

AC:

1244

AN:

86238

European-Finnish (FIN)

AF:

0.0690

AC:

3667

AN:

53124

Middle Eastern (MID)

AF:

0.0422

AC:

242

AN:

5738

European-Non Finnish (NFE)

AF:

0.0484

AC:

53817

AN:

1110940

Other (OTH)

AF:

0.0419

AC:

2527

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3597

7194

10790

14387

17984

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1974

3948

5922

7896

9870

<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:

0.0361

AC:

5494

AN:

152292

Hom.:

146

Cov.:

AF XY:

0.0370

AC XY:

2754

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.00909

AC:

378

AN:

41568

American (AMR)

AF:

0.0388

AC:

593

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0701

AC:

243

AN:

3468

East Asian (EAS)

AF:

0.000771

AC:

AN:

5190

South Asian (SAS)

AF:

0.0128

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0740

AC:

785

AN:

10614

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0487

AC:

3313

AN:

68008

Other (OTH)

AF:

0.0308

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

279

558

837

1116

1395

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

140

210

280

350

<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:

0.0313

Hom.:

Bravo

AF:

0.0323

Asia WGS

AF:

0.00693

AC:

AN:

3478

EpiCase

AF:

0.0565

EpiControl

AF:

0.0562

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

2.8

(source)

DANN

Benign

0.61

PhyloP100

-2.6

PromoterAI

-0.0092

Neutral

(source)

Mutation Taster

=99/1

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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