chr17-44915346-C-T

Variant names:

• chr17-44915346-C-T
• rs2229011
• NM_002055.5:c.141G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5 O:1
• Conservation: PhyloP100: -2.59
• 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: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Alexander disease type II

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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 CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id is 66458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915346-C-T is described in CliVar as Benign. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.141G>A	p.Pro47Pro	synonymous_variant	Exon 1 of 9	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.141G>A	p.Pro47Pro	synonymous_variant	Exon 1 of 10		NP_001350775.1
GFAP	NM_001242376.3	c.141G>A	p.Pro47Pro	synonymous_variant	Exon 1 of 7		NP_001229305.1
GFAP	NM_001131019.3	c.141G>A	p.Pro47Pro	synonymous_variant	Exon 1 of 8		NP_001124491.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.141G>A	p.Pro47Pro	synonymous_variant	Exon 1 of 9	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes AF: 0.0361 AC: 5492 AN: 152174 Hom.: 146 Cov.: 32

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

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.: 32 AF XY: 0.0439 AC XY: 31846 AN XY: 726206

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: 2 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

GnomAD4 genome AF: 0.0361 AC: 5494 AN: 152292 Hom.: 146 Cov.: 32 AF XY: 0.0370 AC XY: 2754 AN XY: 74468

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: 4 AN: 5190

South Asian (SAS) AF: 0.0128 AC: 62 AN: 4826

European-Finnish (FIN) AF: 0.0740 AC: 785 AN: 10614

Middle Eastern (MID) AF: 0.0408 AC: 12 AN: 294

European-Non Finnish (NFE) AF: 0.0487 AC: 3313 AN: 68008

Other (OTH) AF: 0.0308 AC: 65 AN: 2112

Alfa AF: 0.0313 Hom.: 37

Bravo AF: 0.0323

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.0565

EpiControl AF: 0.0562

ClinVar

Significance: Benign

Submissions summary: Benign:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5 Other:1

-

Epithelial Biology; Institute of Medical Biology, Singapore

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Sep 01, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	2.8
DANN	Benign	0.61
PhyloP100		-2.6
PromoterAI		-0.0092	Neutral
Mutation Taster		=99/1	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: rs2229011; hg19: chr17-42992714;