rs9916491

chr17-44910156-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002055.5(GFAP):c.1171+459A>G variant causes a intron 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 NM_002055.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.401

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 1164603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44910156-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
GFAP	NM_002055.5	c.1171+459A>G		intron_variant		ENST00000588735.3
GFAP	NM_001363846.2	c.1276A>G	p.Thr426Ala	missense_variant	8/10
GFAP	NM_001131019.3	c.1276A>G	p.Thr426Ala	missense_variant	8/8
GFAP	NM_001242376.3	c.*313A>G		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.1171+459A>G		intron_variant		1	NM_002055.5	P1

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

GnomAD3 exomes AF: 0.268 AC: 66759 AN: 248826 Hom.: 9227 AF XY: 0.269 AC XY: 36365 AN XY: 135216

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 SAS exome AF: 0.282

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

Gnomad4 AFR exome AF: 0.233

Gnomad4 AMR exome AF: 0.225

Gnomad4 ASJ exome AF: 0.239

Gnomad4 EAS exome AF: 0.219

Gnomad4 SAS exome AF: 0.283

Gnomad4 FIN exome AF: 0.316

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.263

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

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.227

Gnomad4 ASJ AF: 0.242

Gnomad4 EAS AF: 0.253

Gnomad4 SAS AF: 0.271

Gnomad4 FIN AF: 0.318

Gnomad4 NFE AF: 0.280

Gnomad4 OTH AF: 0.261

Alfa AF: 0.270 Hom.: 8882

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	P;P;P
Vest4		0.040
ClinPred		0.0012	T
GERP RS		3.8
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs9916491; hg19: chr17-42987524; COSMIC: COSV53649561; COSMIC: COSV53649561;