rs11584340

Variant names:

• chr1-152313454-G-A
• rs11584340
• NM_002016.2:c.1432C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-152313454-G-A
• chr1-152313454-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002016.2(FLG):​c.1432C>T​(p.Pro478Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,613,236 control chromosomes in the GnomAD database, including 42,398 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (4073 hom., cov: 29)
  • Exomes 𝑓: 0.20 (38325 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.81
• Publications: 56 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0032969E-5).
• BP6: Variant 1-152313454-G-A is Benign according to our data. Variant chr1-152313454-G-A is described in ClinVar as Benign. ClinVar VariationId is 666623.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.574 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	NM_002016.2	MANE Select	c.1432C>T	p.Pro478Ser	missense	Exon 3 of 3	NP_002007.1
	CCDST	NR_186761.1		n.578-19129G>A		intron	N/A
	CCDST	NR_186762.1		n.180-19129G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FLG	ENST00000368799.2	TSL:1 MANE Select	c.1432C>T	p.Pro478Ser	missense	Exon 3 of 3	ENSP00000357789.1
	CCDST	ENST00000665223.1		n.879G>A		non_coding_transcript_exon	Exon 1 of 5
	CCDST	ENST00000420707.5	TSL:5	n.463-1452G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.203 AC: 30769 AN: 151304 Hom.: 4065 Cov.: 29

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.314

Gnomad EAS AF: 0.592

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.187

Gnomad MID AF: 0.264

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.233

GnomAD2 exomes AF: 0.273 AC: 68518 AN: 251380 AF XY: 0.273

Gnomad AFR exome AF: 0.135

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.579

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.253

GnomAD4 exome AF: 0.201 AC: 293476 AN: 1461814 Hom.: 38325 Cov.: 76 AF XY: 0.206 AC XY: 150050 AN XY: 727204

African (AFR) AF: 0.135 AC: 4514 AN: 33418

American (AMR) AF: 0.437 AC: 19532 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.303 AC: 7911 AN: 26136

East Asian (EAS) AF: 0.606 AC: 24049 AN: 39700

South Asian (SAS) AF: 0.411 AC: 35485 AN: 86258

European-Finnish (FIN) AF: 0.177 AC: 9429 AN: 53420

Middle Eastern (MID) AF: 0.292 AC: 1685 AN: 5764

European-Non Finnish (NFE) AF: 0.159 AC: 176584 AN: 1112010

Other (OTH) AF: 0.237 AC: 14287 AN: 60392

GnomAD4 genome AF: 0.203 AC: 30790 AN: 151422 Hom.: 4073 Cov.: 29 AF XY: 0.215 AC XY: 15863 AN XY: 73952

African (AFR) AF: 0.138 AC: 5706 AN: 41248

American (AMR) AF: 0.358 AC: 5457 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.314 AC: 1088 AN: 3466

East Asian (EAS) AF: 0.592 AC: 2979 AN: 5036

South Asian (SAS) AF: 0.434 AC: 2059 AN: 4742

European-Finnish (FIN) AF: 0.187 AC: 1969 AN: 10524

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.159 AC: 10792 AN: 67882

Other (OTH) AF: 0.230 AC: 482 AN: 2100

Alfa AF: 0.187 Hom.: 3370

Bravo AF: 0.215

TwinsUK AF: 0.158 AC: 586

ALSPAC AF: 0.163 AC: 629

ESP6500AA AF: 0.140 AC: 615

ESP6500EA AF: 0.168 AC: 1444

ExAC AF: 0.261 AC: 31705

Asia WGS AF: 0.507 AC: 1761 AN: 3478

EpiCase AF: 0.175

EpiControl AF: 0.171

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ichthyosis vulgaris (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.041
BayesDel_addAF	Benign	-0.88	T
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.0060
DANN	Benign	0.67
DEOGEN2	Benign	0.018	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.00021	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.000010	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.6	N
PhyloP100		-1.8
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Polyphen		0.020	B
Vest4		0.010
ClinPred		0.0078	T
GERP RS		-3.1
Varity_R		0.023
gMVP		0.048
Mutation Taster		=100/0	polymorphism (auto)

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: rs11584340; hg19: chr1-152285930; COSMIC: COSV64239594; COSMIC: COSV64239594;