rs78994946

chr17-44910144-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002055.5(GFAP):c.1171+471C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 1,613,924 control chromosomes in the GnomAD database, including 665 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (54 hom., cov: 31)
  • Exomes 𝑓: 0.027 (611 hom.)
• Consequence: GFAP NM_002055.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 2.96

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070183575).
• BP6: Variant 17-44910144-G-A is Benign according to our data. Variant chr17-44910144-G-A is described in ClinVar as [Benign]. Clinvar id is 66449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44910144-G-A is described in Lovd as [Likely_benign]. Variant chr17-44910144-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3235/152298) while in subpopulation NFE AF= 0.0298 (2030/68038). AF 95% confidence interval is 0.0288. There are 54 homozygotes in gnomad4. There are 1544 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 3233 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GFAP	NM_002055.5	c.1171+471C>T		intron_variant		ENST00000588735.3
GFAP	NM_001363846.2	c.1288C>T	p.Arg430Cys	missense_variant	8/10
GFAP	NM_001131019.3	c.1288C>T	p.Arg430Cys	missense_variant	8/8
GFAP	NM_001242376.3	c.*325C>T		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GFAP	ENST00000588735.3	c.1171+471C>T		intron_variant		1	NM_002055.5	P1

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3233 AN: 152180 Hom.: 54 Cov.: 31

Gnomad AFR AF: 0.00519

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0305

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0306

GnomAD3 exomes AF: 0.0227 AC: 5652 AN: 248848 Hom.: 97 AF XY: 0.0231 AC XY: 3129 AN XY: 135230

Gnomad AFR exome AF: 0.00531

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0295

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0164

Gnomad FIN exome AF: 0.0366

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0269 AC: 39335 AN: 1461626 Hom.: 611 Cov.: 33 AF XY: 0.0269 AC XY: 19558 AN XY: 727104

Gnomad4 AFR exome AF: 0.00424

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.0303

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0171

Gnomad4 FIN exome AF: 0.0360

Gnomad4 NFE exome AF: 0.0294

Gnomad4 OTH exome AF: 0.0251

GnomAD4 genome AF: 0.0212 AC: 3235 AN: 152298 Hom.: 54 Cov.: 31 AF XY: 0.0207 AC XY: 1544 AN XY: 74464

Gnomad4 AFR AF: 0.00517

Gnomad4 AMR AF: 0.0222

Gnomad4 ASJ AF: 0.0305

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0149

Gnomad4 FIN AF: 0.0358

Gnomad4 NFE AF: 0.0298

Gnomad4 OTH AF: 0.0302

Alfa AF: 0.0265 Hom.: 83

Bravo AF: 0.0197

TwinsUK AF: 0.0286 AC: 106

ALSPAC AF: 0.0234 AC: 90

ESP6500AA AF: 0.00606 AC: 19

ESP6500EA AF: 0.0318 AC: 228

ExAC AF: 0.0233 AC: 2806

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.0301

EpiControl AF: 0.0278

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1 Other:1

not provided, no classification provided	literature only	Epithelial Biology; Institute of Medical Biology, Singapore	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jun 29, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.51	T;T
MetaRNN	Benign	0.0065	T;T
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	0.88	D;D;D
Vest4		0.039
ClinPred		0.040	T
GERP RS		3.8
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs78994946; hg19: chr17-42987512;