rs2065956

chr1-152304869-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_002016.2(FLG):c.10017G>A(p.Gln3339=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,613,646 control chromosomes in the GnomAD database, including 33,854 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.16 (3149 hom., cov: 29)
  • Exomes 𝑓: 0.17 (30705 hom.)
• Consequence: FLG NM_002016.2 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.308

Genes affected

FLG (HGNC:3748): (filaggrin) The protein encoded by this gene is an intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. It is initially synthesized as a polyprotein precursor, profilaggrin (consisting of multiple filaggrin units of 324 aa each), which is localized in keratohyalin granules, and is subsequently proteolytically processed into individual functional filaggrin molecules. Mutations in this gene are associated with ichthyosis vulgaris.[provided by RefSeq, Dec 2009]

FLG-AS1 (HGNC:27913): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 1-152304869-C-T is Benign according to our data. Variant chr1-152304869-C-T is described in ClinVar as [Benign]. Clinvar id is 2585647.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-152304869-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.308 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.549 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FLG	NM_002016.2	c.10017G>A	p.Gln3339=	synonymous_variant	3/3	ENST00000368799.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FLG	ENST00000368799.2	c.10017G>A	p.Gln3339=	synonymous_variant	3/3	1	NM_002016.2	P1
FLG-AS1	ENST00000653548.1	n.390-27714C>T		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23751 AN: 151688 Hom.: 3146 Cov.: 29

Gnomad AFR AF: 0.0340

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.292

Gnomad EAS AF: 0.567

Gnomad SAS AF: 0.378

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.195

GnomAD3 exomes AF: 0.243 AC: 61072 AN: 251484 Hom.: 10694 AF XY: 0.243 AC XY: 33022 AN XY: 135914

Gnomad AFR exome AF: 0.0290

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.281

Gnomad EAS exome AF: 0.560

Gnomad SAS exome AF: 0.371

Gnomad FIN exome AF: 0.171

Gnomad NFE exome AF: 0.142

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.173 AC: 253172 AN: 1461840 Hom.: 30705 Cov.: 37 AF XY: 0.178 AC XY: 129525 AN XY: 727218

Gnomad4 AFR exome AF: 0.0265

Gnomad4 AMR exome AF: 0.418

Gnomad4 ASJ exome AF: 0.280

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.359

Gnomad4 FIN exome AF: 0.168

Gnomad4 NFE exome AF: 0.135

Gnomad4 OTH exome AF: 0.206

GnomAD4 genome AF: 0.156 AC: 23751 AN: 151806 Hom.: 3149 Cov.: 29 AF XY: 0.168 AC XY: 12443 AN XY: 74136

Gnomad4 AFR AF: 0.0339

Gnomad4 AMR AF: 0.327

Gnomad4 ASJ AF: 0.292

Gnomad4 EAS AF: 0.566

Gnomad4 SAS AF: 0.377

Gnomad4 FIN AF: 0.178

Gnomad4 NFE AF: 0.135

Gnomad4 OTH AF: 0.192

Alfa AF: 0.141 Hom.: 887

Bravo AF: 0.166

Asia WGS AF: 0.455 AC: 1579 AN: 3476

EpiCase AF: 0.151

EpiControl AF: 0.148

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ichthyosis vulgaris Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.37
Dann	Benign	0.32

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: rs2065956; hg19: chr1-152277345; COSMIC: COSV64237848;