1-152307085-C-T

Variant names:

• chr1-152307085-C-T
• rs146849256
• NM_002016.2:c.7801G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BS2_Supporting

The NM_002016.2(FLG):​c.7801G>A​(p.Asp2601Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,610,448 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 24)
  • Exomes 𝑓: 0.0017 (4 hom.)
• Consequence: FLG NM_002016.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.338

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:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008227736).
• BP6: Variant 1-152307085-C-T is Benign according to our data. Variant chr1-152307085-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445660.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Homozygotes in GnomAdExome4 at 4 SD geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FLG	NM_002016.2	c.7801G>A	p.Asp2601Asn	missense_variant	Exon 3 of 3	ENST00000368799.2	NP_002007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FLG	ENST00000368799.2	c.7801G>A	p.Asp2601Asn	missense_variant	Exon 3 of 3	1	NM_002016.2	ENSP00000357789.1

Frequencies

GnomAD3 genomes AF: 0.00112 AC: 166 AN: 148470 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.000255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000603

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000967

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00211

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.000993 AC: 249 AN: 250844 AF XY: 0.00103

Gnomad AFR exome AF: 0.000316

Gnomad AMR exome AF: 0.000549

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.00188

Gnomad OTH exome AF: 0.000817

GnomAD4 exome AF: 0.00169 AC: 2477 AN: 1461862 Hom.: 4 Cov.: 33 AF XY: 0.00164 AC XY: 1190 AN XY: 727230

Gnomad4 AFR exome AF: 0.000747 AC: 25 AN: 33464

Gnomad4 AMR exome AF: 0.000447 AC: 20 AN: 44722

Gnomad4 ASJ exome AF: 0.0000765 AC: 2 AN: 26136

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86256

Gnomad4 FIN exome AF: 0.000412 AC: 22 AN: 53420

Gnomad4 NFE exome AF: 0.00209 AC: 2319 AN: 1112012

Gnomad4 Remaining exome AF: 0.00147 AC: 89 AN: 60390

GnomAD4 genome AF: 0.00112 AC: 166 AN: 148586 Hom.: 0 Cov.: 24 AF XY: 0.000856 AC XY: 62 AN XY: 72442

Gnomad4 AFR AF: 0.000254 AC: 0.000254427 AN: 0.000254427

Gnomad4 AMR AF: 0.000602 AC: 0.00060241 AN: 0.00060241

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.0000967 AC: 0.0000966931 AN: 0.0000966931

Gnomad4 NFE AF: 0.00211 AC: 0.00211345 AN: 0.00211345

Gnomad4 OTH AF: 0.00145 AC: 0.00145208 AN: 0.00145208

Alfa AF: 0.00148 Hom.: 0

Bravo AF: 0.00124

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00101 AC: 123

EpiCase AF: 0.00196

EpiControl AF: 0.00154

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ichthyosis vulgaris;C1853965:Dermatitis, atopic, 2 Uncertain:1

Jun 30, 2016

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Mar 06, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.0
DANN	Benign	0.73
DEOGEN2	Benign	0.019	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.58	T
M_CAP	Benign	0.0022	T
MetaRNN	Benign	0.0082	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.54	N
REVEL	Benign	0.086
Sift	Benign	0.047	D
Polyphen		0.61	P
Vest4		0.042
MVP		0.12
ClinPred		0.012	T
GERP RS		-2.3
Varity_R		0.035
gMVP		0.034
Mutation Taster		=100/0	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

Publications

LitVar

Other links and lift over

dbSNP: rs146849256; hg19: chr1-152279561;