17-44910156-T-C

Variant names:

• chr17-44910156-T-C
• rs9916491
• ENST00000591327.2:n.2784A>G

Variant summary

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

The ENST00000591327.2(GFAP):​n.2784A>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.272 in 1,613,168 control chromosomes in the GnomAD database, including 59,886 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5268 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54618 hom.)
• Consequence: GFAP ENST00000591327.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.401
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044329464).
• BP6: Variant 17-44910156-T-C is Benign according to our data. Variant chr17-44910156-T-C is described in ClinVar as Benign. ClinVar VariationId is 1164603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.276 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GFAP	NM_002055.5	c.1171+459A>G		intron_variant	Intron 7 of 8	ENST00000588735.3	NP_002046.1
GFAP	NM_001363846.2	c.1276A>G	p.Thr426Ala	missense_variant	Exon 8 of 10		NP_001350775.1
GFAP	NM_001131019.3	c.1276A>G	p.Thr426Ala	missense_variant	Exon 8 of 8		NP_001124491.1
GFAP	NM_001242376.3	c.*313A>G		3_prime_UTR_variant	Exon 7 of 7		NP_001229305.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3	c.1171+459A>G		intron_variant	Intron 7 of 8	1	NM_002055.5	ENSP00000466598.2

Frequencies

GnomAD3 genomes AF: 0.261 AC: 39704 AN: 151990 Hom.: 5263 Cov.: 32

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.227

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.253

Gnomad SAS AF: 0.272

Gnomad FIN AF: 0.318

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.280

Gnomad OTH AF: 0.264

GnomAD2 exomes AF: 0.268 AC: 66759 AN: 248826 AF XY: 0.269

Gnomad AFR exome AF: 0.232

Gnomad AMR exome AF: 0.224

Gnomad ASJ exome AF: 0.245

Gnomad EAS exome AF: 0.254

Gnomad FIN exome AF: 0.322

Gnomad NFE exome AF: 0.277

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.273 AC: 398413 AN: 1461060 Hom.: 54618 Cov.: 35 AF XY: 0.273 AC XY: 198762 AN XY: 726842

African (AFR) AF: 0.233 AC: 7802 AN: 33468

American (AMR) AF: 0.225 AC: 10085 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6248 AN: 26132

East Asian (EAS) AF: 0.219 AC: 8685 AN: 39700

South Asian (SAS) AF: 0.283 AC: 24366 AN: 86248

European-Finnish (FIN) AF: 0.316 AC: 16870 AN: 53398

Middle Eastern (MID) AF: 0.267 AC: 1540 AN: 5768

European-Non Finnish (NFE) AF: 0.276 AC: 306919 AN: 1111264

Other (OTH) AF: 0.263 AC: 15898 AN: 60358

GnomAD4 genome AF: 0.261 AC: 39731 AN: 152108 Hom.: 5268 Cov.: 32 AF XY: 0.261 AC XY: 19394 AN XY: 74350

African (AFR) AF: 0.232 AC: 9617 AN: 41500

American (AMR) AF: 0.227 AC: 3467 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 839 AN: 3466

East Asian (EAS) AF: 0.253 AC: 1306 AN: 5170

South Asian (SAS) AF: 0.271 AC: 1308 AN: 4828

European-Finnish (FIN) AF: 0.318 AC: 3356 AN: 10564

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

European-Non Finnish (NFE) AF: 0.280 AC: 19007 AN: 67972

Other (OTH) AF: 0.261 AC: 552 AN: 2112

Alfa AF: 0.267 Hom.: 12710

Bravo AF: 0.253

TwinsUK AF: 0.259 AC: 960

ALSPAC AF: 0.260 AC: 1003

ESP6500AA AF: 0.241 AC: 756

ESP6500EA AF: 0.274 AC: 1965

ExAC AF: 0.267 AC: 32176

Asia WGS AF: 0.228 AC: 790 AN: 3478

EpiCase AF: 0.270

EpiControl AF: 0.261

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.20	T;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		0.40
PROVEAN	Benign	-0.41	.;N
REVEL	Benign	0.16
Sift	Benign	0.14	.;T
Sift4G	Benign	0.22	.;T
Vest4		0.040
ClinPred		0.0012	T
GERP RS		3.8
gMVP		0.26
Mutation Taster		=98/2	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: rs9916491; hg19: chr17-42987524; COSMIC: COSV53649561; COSMIC: COSV53649561;