chr17-44907331-C-T

Variant names:

• chr17-44907331-C-T
• rs113487550
• NM_002055.5:c.*16G>A

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.*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:4
• Conservation: PhyloP100: 0.410
• Publications: 6 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=-0.69).
• BP6: Variant 17-44907331-C-T is Benign according to our data. Variant chr17-44907331-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3602 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.*16G>A		3_prime_UTR	Exon 9 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.*16G>A		3_prime_UTR	Exon 10 of 10	NP_001350775.1	A0A1X7SBR3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.*16G>A		3_prime_UTR	Exon 9 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000585543.6	TSL:1	n.468G>A		non_coding_transcript_exon	Exon 4 of 4
	GFAP	ENST00000253408.11	TSL:5	c.*16G>A		3_prime_UTR	Exon 10 of 10	ENSP00000253408.5	A0A1X7SBR3

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

GnomAD2 exomes AF: 0.0238 AC: 5977 AN: 251214 AF XY: 0.0239

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 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

African (AFR) AF: 0.00526 AC: 176 AN: 33458

American (AMR) AF: 0.0133 AC: 595 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0104 AC: 273 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.00973 AC: 839 AN: 86232

European-Finnish (FIN) AF: 0.0394 AC: 2106 AN: 53406

Middle Eastern (MID) AF: 0.0103 AC: 59 AN: 5706

European-Non Finnish (NFE) AF: 0.0363 AC: 40289 AN: 1110316

Other (OTH) AF: 0.0255 AC: 1540 AN: 60312

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

African (AFR) AF: 0.00578 AC: 240 AN: 41522

American (AMR) AF: 0.0174 AC: 266 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00951 AC: 33 AN: 3470

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

South Asian (SAS) AF: 0.00871 AC: 42 AN: 4824

European-Finnish (FIN) AF: 0.0402 AC: 426 AN: 10608

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.0374 AC: 2542 AN: 67988

Other (OTH) AF: 0.0199 AC: 42 AN: 2112

Alfa AF: 0.0331 Hom.: 58

Bravo AF: 0.0208

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	Alexander disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	13
DANN	Benign	0.80
PhyloP100		0.41
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: rs113487550; hg19: chr17-42984699;