rs59291670

Variant names:

• chr17-44914081-C-T
• rs59291670
• NM_002055.5:c.469G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-44914081-C-T
• chr17-44914081-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002055.5(GFAP):​c.469G>A​(p.Asp157Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0165 in 1,549,378 control chromosomes in the GnomAD database, including 282 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (16 hom., cov: 32)
  • Exomes 𝑓: 0.017 (266 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7 O:1
• Conservation: PhyloP100: 3.80
• Publications: 20 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 (MetaRNN=0.0133288205).
• BP6: Variant 17-44914081-C-T is Benign according to our data. Variant chr17-44914081-C-T is described in ClinVar as Benign. ClinVar VariationId is 66485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1658/152104) while in subpopulation NFE AF = 0.0173 (1179/67984). AF 95% confidence interval is 0.0165. There are 16 homozygotes in GnomAd4. There are 789 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1658 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.469G>A	p.Asp157Asn	missense	Exon 2 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.469G>A	p.Asp157Asn	missense	Exon 2 of 10	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.469G>A	p.Asp157Asn	missense	Exon 2 of 7	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.469G>A	p.Asp157Asn	missense	Exon 2 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.1419G>A		non_coding_transcript_exon	Exon 1 of 5
	GFAP	ENST00000639277.1	TSL:5	c.469G>A	p.Asp157Asn	missense	Exon 2 of 10	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1657 AN: 151986 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.00310

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00583

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0182

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0173

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0109 AC: 1746 AN: 159742 AF XY: 0.0103

Gnomad AFR exome AF: 0.00330

Gnomad AMR exome AF: 0.00493

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0165

Gnomad NFE exome AF: 0.0189

Gnomad OTH exome AF: 0.00918

GnomAD4 exome AF: 0.0171 AC: 23837 AN: 1397274 Hom.: 266 Cov.: 30 AF XY: 0.0166 AC XY: 11443 AN XY: 689466

African (AFR) AF: 0.00296 AC: 94 AN: 31708

American (AMR) AF: 0.00494 AC: 177 AN: 35850

Ashkenazi Jewish (ASJ) AF: 0.00909 AC: 228 AN: 25080

East Asian (EAS) AF: 0.00 AC: 0 AN: 35976

South Asian (SAS) AF: 0.00101 AC: 80 AN: 79362

European-Finnish (FIN) AF: 0.0165 AC: 805 AN: 48760

Middle Eastern (MID) AF: 0.00447 AC: 25 AN: 5596

European-Non Finnish (NFE) AF: 0.0201 AC: 21686 AN: 1077092

Other (OTH) AF: 0.0128 AC: 742 AN: 57850

GnomAD4 genome AF: 0.0109 AC: 1658 AN: 152104 Hom.: 16 Cov.: 32 AF XY: 0.0106 AC XY: 789 AN XY: 74392

African (AFR) AF: 0.00309 AC: 128 AN: 41476

American (AMR) AF: 0.00582 AC: 89 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00125 AC: 6 AN: 4814

European-Finnish (FIN) AF: 0.0182 AC: 193 AN: 10576

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0173 AC: 1179 AN: 67984

Other (OTH) AF: 0.0104 AC: 22 AN: 2114

Alfa AF: 0.0164 Hom.: 44

Bravo AF: 0.0107

TwinsUK AF: 0.0205 AC: 76

ALSPAC AF: 0.0179 AC: 69

ESP6500AA AF: 0.00620 AC: 27

ESP6500EA AF: 0.0142 AC: 121

ExAC AF: 0.00690 AC: 741

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (6)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.080	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.8
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.37
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.024	D
Polyphen		0.0040	B
Vest4		0.26
MPC		0.78
ClinPred		0.020	T
GERP RS		4.6
Varity_R		0.35
gMVP		0.32
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59291670; hg19: chr17-42991449;