rs57474185

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002055.5(GFAP):c.140C>T(p.Pro47Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00682 in 1,612,262 control chromosomes in the GnomAD database, including 47 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P47P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0053 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 45 hom. )

Consequence

GFAP
NM_002055.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9O:1

Conservation

PhyloP100: 2.09

Variant links:

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 links:

GFAP (HGNC:):

GFAP links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006749183).

BP6

Variant 17-44915347-G-A is Benign according to our data. Variant chr17-44915347-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 66457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44915347-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00532 (810/152348) while in subpopulation NFE AF= 0.00955 (650/68040). AF 95% confidence interval is 0.00894. There are 2 homozygotes in gnomad4. There are 376 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 810 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GFAP	NM_002055.5 linkuse as main transcript	c.140C>T	p.Pro47Leu	missense_variant	1/9	ENST00000588735.3	NP_002046.1	P14136-1
GFAP	NM_001363846.2 linkuse as main transcript	c.140C>T	p.Pro47Leu	missense_variant	1/10		NP_001350775.1
GFAP	NM_001242376.3 linkuse as main transcript	c.140C>T	p.Pro47Leu	missense_variant	1/7		NP_001229305.1	P14136-2
GFAP	NM_001131019.3 linkuse as main transcript	c.140C>T	p.Pro47Leu	missense_variant	1/8		NP_001124491.1	P14136-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GFAP	ENST00000588735.3 linkuse as main transcript	c.140C>T	p.Pro47Leu	missense_variant	1/9	1	NM_002055.5	ENSP00000466598.2		P14136-1

Frequencies

GnomAD3 genomes

AF:

0.00532

AC:

810

AN:

152230

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00268

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.00235

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00955

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00493

AC:

1230

AN:

249678

Hom.:

AF XY:

0.00484

AC XY:

655

AN XY:

135288

show subpopulations

Gnomad AFR exome

AF:

0.00126

Gnomad AMR exome

AF:

0.00307

Gnomad ASJ exome

AF:

0.00838

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00144

Gnomad FIN exome

AF:

0.00334

Gnomad NFE exome

AF:

0.00781

Gnomad OTH exome

AF:

0.00393

GnomAD4 exome

AF:

0.00697

AC:

10180

AN:

1459914

Hom.:

Cov.:

AF XY:

0.00680

AC XY:

4934

AN XY:

725886

show subpopulations

Gnomad4 AFR exome

AF:

0.000837

Gnomad4 AMR exome

AF:

0.00293

Gnomad4 ASJ exome

AF:

0.00796

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00145

Gnomad4 FIN exome

AF:

0.00305

Gnomad4 NFE exome

AF:

0.00821

Gnomad4 OTH exome

AF:

0.00658

GnomAD4 genome

AF:

0.00532

AC:

810

AN:

152348

Hom.:

Cov.:

AF XY:

0.00505

AC XY:

376

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.00268

Gnomad4 ASJ

AF:

0.00749

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000828

Gnomad4 FIN

AF:

0.00235

Gnomad4 NFE

AF:

0.00955

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00803

Hom.:

Bravo

AF:

0.00470

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0101

AC:

ExAC

AF:

0.00502

AC:

609

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00731

EpiControl

AF:

0.00682

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6Other:1

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 29, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 08, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GFAP: BS2 -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Dec 29, 2023

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 14, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Alexander disease

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

DANN

Benign

0.80

DEOGEN2

Benign

0.29

.;T;.;.;.;T;.;.;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.72

LIST_S2

Uncertain

0.92

D;D;D;D;D;D;D;D;D

MetaRNN

Benign

0.0067

T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

2.0

.;M;.;M;M;.;.;.;.

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-0.61

.;.;N;N;.;.;.;.;.

REVEL

Uncertain

0.49

Sift

Benign

0.34

.;.;T;T;.;.;.;.;.

Sift4G

Benign

0.17

.;.;T;T;.;T;T;.;.

Polyphen

0.021

.;B;.;.;.;.;.;.;.

Vest4

0.39, 0.41

MVP

0.95

MPC

0.60

ClinPred

0.019

GERP RS

4.8

Varity_R

0.19

gMVP

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over