rs147282497

Positions:

• chr17-44915158-G-C

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002055.5(GFAP):​c.329C>G​(p.Thr110Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000203 in 1,614,160 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T110A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (3 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:4
• Conservation: PhyloP100: 6.31

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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08596799).
• BP6: Variant 17-44915158-G-C is Benign according to our data. Variant chr17-44915158-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 323625.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr17-44915158-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000223 (34/152328) while in subpopulation AMR AF= 0.000849 (13/15312). AF 95% confidence interval is 0.000502. There are 1 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.329C>G	p.Thr110Ser	missense_variant	1/9	ENST00000588735.3
GFAP	NM_001363846.2	c.329C>G	p.Thr110Ser	missense_variant	1/10
GFAP	NM_001242376.3	c.329C>G	p.Thr110Ser	missense_variant	1/7
GFAP	NM_001131019.3	c.329C>G	p.Thr110Ser	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.329C>G	p.Thr110Ser	missense_variant	1/9	1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152212 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000259 AC: 65 AN: 251384 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000211

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000201 AC: 294 AN: 1461832 Hom.: 3 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 727226

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000626

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.000580

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000255 AC: 31

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	GFAP: BP4, BS1 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Alexander disease Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	New York Genome Center	Jul 10, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	20
DANN	Benign	0.31
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.075
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.74	T;T;T;T;T;T;T;T;T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.086	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.50	T
Polyphen		0.0020	.;B;.;.;.;.;.;.;.
Vest4		0.12, 0.15, 0.14
MutPred		0.36		Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);Gain of phosphorylation at T110 (P = 0.1007);
MVP		0.97
MPC		0.38
ClinPred		0.054	T
GERP RS		4.7
Varity_R		0.38
gMVP		0.29

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: rs147282497; hg19: chr17-42992526;