17-44906533-A-T

Variant names:

• chr17-44906533-A-T
• rs3744470
• NM_002055.5:c.*814T>A

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.*814T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.122 in 152,462 control chromosomes in the GnomAD database, including 1,229 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1226 hom., cov: 32)
  • Exomes 𝑓: 0.097 (3 hom.)
• Consequence: GFAP NM_002055.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.190
• Publications: 9 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 (BayesDel_noAF=-0.8).
• BP6: Variant 17-44906533-A-T is Benign according to our data. Variant chr17-44906533-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 323601.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.233 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	NM_002055.5	MANE Select	c.*814T>A		3_prime_UTR	Exon 9 of 9	NP_002046.1
	GFAP	NM_001363846.2		c.*814T>A		3_prime_UTR	Exon 10 of 10	NP_001350775.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.*814T>A		3_prime_UTR	Exon 9 of 9	ENSP00000466598.2
	GFAP	ENST00000638921.1	TSL:6	n.1715T>A		non_coding_transcript_exon	Exon 1 of 1
	GFAP	ENST00000253408.11	TSL:5	c.*814T>A		3_prime_UTR	Exon 10 of 10	ENSP00000253408.5

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18583 AN: 151964 Hom.: 1225 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0519

Gnomad EAS AF: 0.244

Gnomad SAS AF: 0.112

Gnomad FIN AF: 0.168

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.125

GnomAD4 exome AF: 0.0974 AC: 37 AN: 380 Hom.: 3 Cov.: 0 AF XY: 0.0938 AC XY: 18 AN XY: 192

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.182 AC: 4 AN: 22

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.167 AC: 1 AN: 6

European-Finnish (FIN) AF: 0.154 AC: 4 AN: 26

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0909 AC: 28 AN: 308

Other (OTH) AF: 0.00 AC: 0 AN: 12

GnomAD4 genome AF: 0.122 AC: 18599 AN: 152082 Hom.: 1226 Cov.: 32 AF XY: 0.125 AC XY: 9283 AN XY: 74356

African (AFR) AF: 0.121 AC: 5035 AN: 41470

American (AMR) AF: 0.130 AC: 1990 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0519 AC: 180 AN: 3470

East Asian (EAS) AF: 0.244 AC: 1258 AN: 5152

South Asian (SAS) AF: 0.112 AC: 540 AN: 4826

European-Finnish (FIN) AF: 0.168 AC: 1775 AN: 10588

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7502 AN: 67972

Other (OTH) AF: 0.125 AC: 265 AN: 2112

Alfa AF: 0.0448 Hom.: 53

Bravo AF: 0.121

Asia WGS AF: 0.139 AC: 484 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.5
DANN	Benign	0.57
PhyloP100		0.19
Mutation Taster		=100/0	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: rs3744470; hg19: chr17-42983901;