chr1-152311564-CT-C

Variant names:

• chr1-152311564-CT-C
• rs200519781
• NM_002016.2:c.3321delA

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 16P and 1B. PVS1 PP5_Very_Strong BS2_Supporting

The NM_002016.2(FLG):​c.3321delA​(p.Gly1109GlufsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,614,004 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00022 (3 hom.)
• Consequence: FLG NM_002016.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: -0.436
• Publications: 80 publications found

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]

CCDST (HGNC:55988): (cervical cancer associated DHX9 suppressive transcript)

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 177 pathogenic variants in the truncated region.
• PP5: Variant 1-152311564-CT-C is Pathogenic according to our data. Variant chr1-152311564-CT-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 420115.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 SD,XL,AR,AD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002016.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	NM_002016.2	MANE Select	c.3321delA	p.Gly1109GlufsTer13	frameshift	Exon 3 of 3	NP_002007.1
	CCDST	NR_186761.1		n.578-21018delT		intron	N/A
	CCDST	NR_186762.1		n.180-21018delT		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.3321delA	p.Gly1109GlufsTer13	frameshift	Exon 3 of 3	ENSP00000357789.1
	CCDST	ENST00000420707.5	TSL:5	n.463-3341delT		intron	N/A
	CCDST	ENST00000593011.5	TSL:4	n.377-3341delT		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152010 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000728 AC: 183 AN: 251488 AF XY: 0.000640

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00973

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000220 AC: 321 AN: 1461876 Hom.: 3 Cov.: 112 AF XY: 0.000216 AC XY: 157 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00751 AC: 298 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112004

Other (OTH) AF: 0.000199 AC: 12 AN: 60394

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152128 Hom.: 0 Cov.: 31 AF XY: 0.000350 AC XY: 26 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41524

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00998 AC: 51 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000684

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Ichthyosis vulgaris (7)
3	-	-	not provided (3)
2	-	-	Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 (2)
1	-	-	Autosomal dominant ichthyosis vulgaris (1)
1	-	-	Dermatitis, atopic, 2 (1)
-	-	-	Dermatitis, atopic, 2, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.44
Mutation Taster		=3/197	disease causing (ClinVar)

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: rs200519781; hg19: chr1-152284040;