rs57474185

Variant names:

• chr17-44915347-G-A
• rs57474185
• NM_002055.5:c.140C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-44915347-G-A
• chr17-44915347-G-C
• chr17-44915347-G-T

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.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 Benign.

• Frequency:
  • Genomes: 𝑓 0.0053 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (45 hom.)
• Consequence: GFAP NM_002055.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9 O:1
• Conservation: PhyloP100: 2.09
• Publications: 13 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 (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 Benign/Likely_benign. ClinVar VariationId is 66457.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 = 0.00532 (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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 810 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.140C>T	p.Pro47Leu	missense	Exon 1 of 9	NP_002046.1	P14136-1
	GFAP	NM_001363846.2		c.140C>T	p.Pro47Leu	missense	Exon 1 of 10	NP_001350775.1	A0A1X7SBR3
	GFAP	NM_001242376.3		c.140C>T	p.Pro47Leu	missense	Exon 1 of 7	NP_001229305.1	P14136-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GFAP	ENST00000588735.3	TSL:1 MANE Select	c.140C>T	p.Pro47Leu	missense	Exon 1 of 9	ENSP00000466598.2	P14136-1
	GFAP	ENST00000591327.2	TSL:1	n.153C>T		non_coding_transcript_exon	Exon 1 of 5
	GFAP	ENST00000639277.1	TSL:5	c.140C>T	p.Pro47Leu	missense	Exon 1 of 10	ENSP00000492432.1	A0A1W2PR46

Frequencies

GnomAD3 genomes AF: 0.00532 AC: 810 AN: 152230 Hom.: 2 Cov.: 32

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

GnomAD2 exomes AF: 0.00493 AC: 1230 AN: 249678 AF XY: 0.00484

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 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.: 45 Cov.: 31 AF XY: 0.00680 AC XY: 4934 AN XY: 725886

African (AFR) AF: 0.000837 AC: 28 AN: 33464

American (AMR) AF: 0.00293 AC: 131 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00796 AC: 208 AN: 26120

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39666

South Asian (SAS) AF: 0.00145 AC: 125 AN: 86226

European-Finnish (FIN) AF: 0.00305 AC: 162 AN: 53096

Middle Eastern (MID) AF: 0.00244 AC: 14 AN: 5736

European-Non Finnish (NFE) AF: 0.00821 AC: 9114 AN: 1110616

Other (OTH) AF: 0.00658 AC: 397 AN: 60300

GnomAD4 genome AF: 0.00532 AC: 810 AN: 152348 Hom.: 2 Cov.: 32 AF XY: 0.00505 AC XY: 376 AN XY: 74506

African (AFR) AF: 0.00120 AC: 50 AN: 41566

American (AMR) AF: 0.00268 AC: 41 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00235 AC: 25 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00955 AC: 650 AN: 68040

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00696 Hom.: 2

Bravo AF: 0.00470

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.0101 AC: 87

ExAC AF: 0.00502 AC: 609

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00731

EpiControl AF: 0.00682

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (7)
-	-	1	Alexander disease (1)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	24
DANN	Benign	0.80
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0067	T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	2.0	M
PhyloP100		2.1
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.61	N
REVEL	Uncertain	0.49
Sift	Benign	0.34	T
Sift4G	Benign	0.17	T
Polyphen		0.021	B
Vest4		0.39
MVP		0.95
MPC		0.60
ClinPred		0.019	T
GERP RS		4.8
PromoterAI		-0.0068	Neutral
Varity_R		0.19
gMVP		0.70
Mutation Taster		=99/1	polymorphism

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: rs57474185; hg19: chr17-42992715;