ENST00000591327.2:n.2796C>T

Variant names:

• chr17-44910144-G-A
• rs78994946
• ENST00000591327.2:n.2796C>T

Variant summary

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

The ENST00000591327.2(GFAP):​n.2796C>T 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 0.0264 in 1,613,924 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (54 hom., cov: 31)
  • Exomes 𝑓: 0.027 (611 hom.)
• Consequence: GFAP ENST00000591327.2 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: 2.96
• Publications: 8 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=0.0070183575).
• BP6: Variant 17-44910144-G-A is Benign according to our data. Variant chr17-44910144-G-A is described in ClinVar as Benign. ClinVar VariationId is 66449.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 = 0.0212 (3235/152298) while in subpopulation NFE AF = 0.0298 (2030/68038). AF 95% confidence interval is 0.0288. There are 54 homozygotes in GnomAd4. There are 1544 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3235 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000591327.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.1171+471C>T		intron	N/A	NP_002046.1
	GFAP	NM_001363846.2		c.1288C>T	p.Arg430Cys	missense	Exon 8 of 10	NP_001350775.1
	GFAP	NM_001131019.3		c.1288C>T	p.Arg430Cys	missense	Exon 8 of 8	NP_001124491.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000591327.2	TSL:1	n.2796C>T		non_coding_transcript_exon	Exon 5 of 5
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.1171+471C>T		intron	N/A	ENSP00000466598.2
	GFAP	ENST00000585543.6	TSL:1	n.324+471C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3233 AN: 152180 Hom.: 54 Cov.: 31

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0227 AC: 5652 AN: 248848 AF XY: 0.0231

Gnomad AFR exome AF: 0.00531

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0269 AC: 39335 AN: 1461626 Hom.: 611 Cov.: 33 AF XY: 0.0269 AC XY: 19558 AN XY: 727104

African (AFR) AF: 0.00424 AC: 142 AN: 33478

American (AMR) AF: 0.0152 AC: 678 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0303 AC: 792 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.0171 AC: 1476 AN: 86256

European-Finnish (FIN) AF: 0.0360 AC: 1924 AN: 53402

Middle Eastern (MID) AF: 0.0189 AC: 109 AN: 5768

European-Non Finnish (NFE) AF: 0.0294 AC: 32693 AN: 1111792

Other (OTH) AF: 0.0251 AC: 1516 AN: 60372

GnomAD4 genome AF: 0.0212 AC: 3235 AN: 152298 Hom.: 54 Cov.: 31 AF XY: 0.0207 AC XY: 1544 AN XY: 74464

African (AFR) AF: 0.00517 AC: 215 AN: 41562

American (AMR) AF: 0.0222 AC: 339 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0305 AC: 106 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4826

European-Finnish (FIN) AF: 0.0358 AC: 380 AN: 10608

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2030 AN: 68038

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0263 Hom.: 164

Bravo AF: 0.0197

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00606 AC: 19

ESP6500EA AF: 0.0318 AC: 228

ExAC AF: 0.0233 AC: 2806

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0301

EpiControl AF: 0.0278

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	21
DANN	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0065	T
MetaSVM	Benign	-0.70	T
PhyloP100		3.0
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.35
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.015	D
Vest4		0.039
ClinPred		0.040	T
GERP RS		3.8
gMVP		0.50
Mutation Taster		=56/44	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs78994946; hg19: chr17-42987512; COSMIC: COSV107271685; COSMIC: COSV107271685;