17-44907331-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002055.5(GFAP):c.*16G>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 0.0307 in 1,612,176 control chromosomes in the GnomAD database, including 880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (61 hom., cov: 32)
  • Exomes 𝑓: 0.031 (819 hom.)
• Consequence: GFAP NM_002055.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.410

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 (BayesDel_noAF=-0.69).
• BP6: Variant 17-44907331-C-T is Benign according to our data. Variant chr17-44907331-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 323608.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 = 0.0237 (3602/152198) while in subpopulation NFE AF= 0.0374 (2542/67988). AF 95% confidence interval is 0.0362. There are 61 homozygotes in gnomad4. There are 1726 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3603 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.*16G>A		3_prime_UTR_variant	9/9	ENST00000588735.3
GFAP	NM_001363846.2	c.*16G>A		3_prime_UTR_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.*16G>A		3_prime_UTR_variant	9/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3603 AN: 152080 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00580

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0174

Gnomad ASJ AF: 0.00951

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00870

Gnomad FIN AF: 0.0402

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0374

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.0238 AC: 5977 AN: 251214 Hom.: 97 AF XY: 0.0239 AC XY: 3244 AN XY: 135816

Gnomad AFR exome AF: 0.00523

Gnomad AMR exome AF: 0.0126

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00977

Gnomad FIN exome AF: 0.0403

Gnomad NFE exome AF: 0.0354

Gnomad OTH exome AF: 0.0258

GnomAD4 exome AF: 0.0314 AC: 45879 AN: 1459978 Hom.: 819 Cov.: 31 AF XY: 0.0310 AC XY: 22536 AN XY: 726416

Gnomad4 AFR exome AF: 0.00526

Gnomad4 AMR exome AF: 0.0133

Gnomad4 ASJ exome AF: 0.0104

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00973

Gnomad4 FIN exome AF: 0.0394

Gnomad4 NFE exome AF: 0.0363

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0237 AC: 3602 AN: 152198 Hom.: 61 Cov.: 32 AF XY: 0.0232 AC XY: 1726 AN XY: 74404

Gnomad4 AFR AF: 0.00578

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00951

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00871

Gnomad4 FIN AF: 0.0402

Gnomad4 NFE AF: 0.0374

Gnomad4 OTH AF: 0.0199

Alfa AF: 0.0326 Hom.: 29

Bravo AF: 0.0208

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 30, 2016	- -

Alexander disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	13
Dann	Benign	0.80

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: rs113487550; hg19: chr17-42984699;