rs1126642

Positions:

• chr17-44911695-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_002055.5(GFAP):​c.883G>A​(p.Asp295Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0421 in 1,613,504 control chromosomes in the GnomAD database, including 1,847 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.036 (152 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1695 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 6.17

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 -18 ACMG points.

• PM1: In a region_of_interest Coil 2B (size 120) in uniprot entity GFAP_HUMAN there are 27 pathogenic changes around while only 6 benign (82%) in NM_002055.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.003569454).
• BP6: Variant 17-44911695-C-T is Benign according to our data. Variant chr17-44911695-C-T is described in ClinVar as [Benign]. Clinvar id is 66509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44911695-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.883G>A	p.Asp295Asn	missense_variant	5/9	ENST00000588735.3
GFAP	NM_001363846.2	c.883G>A	p.Asp295Asn	missense_variant	5/10
GFAP	NM_001242376.3	c.883G>A	p.Asp295Asn	missense_variant	5/7
GFAP	NM_001131019.3	c.883G>A	p.Asp295Asn	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.883G>A	p.Asp295Asn	missense_variant	5/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.0356 AC: 5419 AN: 152234 Hom.: 147 Cov.: 33

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0478

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.0602

Gnomad FIN AF: 0.0140

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0393

Gnomad OTH AF: 0.0239

GnomAD3 exomes AF: 0.0454 AC: 11291 AN: 248574 Hom.: 391 AF XY: 0.0458 AC XY: 6161 AN XY: 134604

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.0417

Gnomad ASJ exome AF: 0.0461

Gnomad EAS exome AF: 0.143

Gnomad SAS exome AF: 0.0580

Gnomad FIN exome AF: 0.0129

Gnomad NFE exome AF: 0.0373

Gnomad OTH exome AF: 0.0353

GnomAD4 exome AF: 0.0428 AC: 62509 AN: 1461152 Hom.: 1695 Cov.: 33 AF XY: 0.0428 AC XY: 31148 AN XY: 726966

Gnomad4 AFR exome AF: 0.0198

Gnomad4 AMR exome AF: 0.0428

Gnomad4 ASJ exome AF: 0.0454

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.0566

Gnomad4 FIN exome AF: 0.0145

Gnomad4 NFE exome AF: 0.0401

Gnomad4 OTH exome AF: 0.0421

GnomAD4 genome AF: 0.0356 AC: 5428 AN: 152352 Hom.: 152 Cov.: 33 AF XY: 0.0349 AC XY: 2603 AN XY: 74498

Gnomad4 AFR AF: 0.0223

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0478

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.0598

Gnomad4 FIN AF: 0.0140

Gnomad4 NFE AF: 0.0393

Gnomad4 OTH AF: 0.0237

Alfa AF: 0.0405 Hom.: 328

Bravo AF: 0.0369

TwinsUK AF: 0.0429 AC: 159

ALSPAC AF: 0.0444 AC: 171

ESP6500AA AF: 0.0223 AC: 98

ESP6500EA AF: 0.0377 AC: 324

ExAC AF: 0.0447 AC: 5422

Asia WGS AF: 0.0950 AC: 331 AN: 3478

EpiCase AF: 0.0358

EpiControl AF: 0.0311

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4 Other:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 14, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	30
DANN	Uncertain	1.0
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D
MetaRNN	Benign	0.0036	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.0000052	P;P;P;P
PrimateAI	Uncertain	0.63	T
Polyphen		0.99	.;D;.;.;.;.;.;.
Vest4		0.36, 0.39, 0.21
MPC		1.2
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.83
gMVP		0.96

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: rs1126642; hg19: chr17-42989063; COSMIC: COSV53650087; COSMIC: COSV53650087;