17-44913439-G-C

Variant names:

• chr17-44913439-G-C
• rs3744469
• NM_002055.5:c.619-9C>G

Variant summary

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

The NM_002055.5(GFAP):​c.619-9C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00432 in 1,613,650 control chromosomes in the GnomAD database, including 212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0062 (31 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (181 hom.)
• Consequence: GFAP NM_002055.5 intron
• Scores: Splicing: ADA: 0.009794
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.42
• Publications: 1 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen, 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 (BayesDel_noAF=-0.8).
• BP6: Variant 17-44913439-G-C is Benign according to our data. Variant chr17-44913439-G-C is described in ClinVar as Benign. ClinVar VariationId is 323617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0666 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.619-9C>G		intron	N/A	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.619-9C>G		intron	N/A	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.619-9C>G		intron	N/A	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.619-9C>G		intron	N/A	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.1773-9C>G		intron	N/A
	GFAP	ENST00000639277.1	TSL:5	c.619-9C>G		intron	N/A	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes AF: 0.00611 AC: 930 AN: 152180 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0382

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.0459

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000514

Gnomad OTH AF: 0.00430

GnomAD2 exomes AF: 0.0112 AC: 2796 AN: 250172 AF XY: 0.00931

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.0520

Gnomad ASJ exome AF: 0.00328

Gnomad EAS exome AF: 0.0396

Gnomad FIN exome AF: 0.00182

Gnomad NFE exome AF: 0.000770

Gnomad OTH exome AF: 0.00884

GnomAD4 exome AF: 0.00413 AC: 6039 AN: 1461352 Hom.: 181 Cov.: 32 AF XY: 0.00392 AC XY: 2849 AN XY: 726974

African (AFR) AF: 0.000179 AC: 6 AN: 33470

American (AMR) AF: 0.0503 AC: 2248 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00348 AC: 91 AN: 26132

East Asian (EAS) AF: 0.0688 AC: 2730 AN: 39700

South Asian (SAS) AF: 0.00220 AC: 190 AN: 86214

European-Finnish (FIN) AF: 0.00231 AC: 123 AN: 53356

Middle Eastern (MID) AF: 0.000358 AC: 2 AN: 5584

European-Non Finnish (NFE) AF: 0.000310 AC: 345 AN: 1111848

Other (OTH) AF: 0.00504 AC: 304 AN: 60346

GnomAD4 genome AF: 0.00616 AC: 938 AN: 152298 Hom.: 31 Cov.: 33 AF XY: 0.00743 AC XY: 553 AN XY: 74468

African (AFR) AF: 0.000361 AC: 15 AN: 41568

American (AMR) AF: 0.0385 AC: 589 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.0456 AC: 236 AN: 5174

South Asian (SAS) AF: 0.00290 AC: 14 AN: 4822

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000515 AC: 35 AN: 68026

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00207 Hom.: 2

Bravo AF: 0.00784

Asia WGS AF: 0.0210 AC: 72 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.9
DANN	Benign	0.60
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0098
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.020		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: rs3744469; hg19: chr17-42990807; COSMIC: COSV53648874; COSMIC: COSV53648874;