chr2-69960946-C-T

Variant names:

• chr2-69960946-C-T
• rs1435874677
• NM_152792.4:c.491G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_152792.4(ASPRV1):​c.491G>A​(p.Gly164Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ASPRV1 NM_152792.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.40
• Publications: 0 publications found

Genes affected

ASPRV1 (HGNC:26321): (aspartic peptidase retroviral like 1) Filaggrin is a structural protein that is crucial for in the development and maintenance of the skin barrier. This gene encodes a retroviral-like protease involved in profilaggrin-to-filaggrin processing. Expression is found primarily in the epidermis and inner root sheath of hair follicles. [provided by RefSeq, May 2017]

ASPRV1 Gene-Disease associations (from GenCC):

• ichthyosis, lamellar, autosomal dominant

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics, G2P

ENSG00000293615 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.916

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_152792.4. 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
	ASPRV1	NM_152792.4	MANE Select	c.491G>A	p.Gly164Asp	missense	Exon 1 of 1	NP_690005.3	Q53RT3-2
	ASPRV1	NR_170631.1		n.3034G>A		non_coding_transcript_exon	Exon 5 of 5
	ASPRV1	NR_170632.1		n.3184G>A		non_coding_transcript_exon	Exon 6 of 6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASPRV1	ENST00000320256.6	TSL:6 MANE Select	c.491G>A	p.Gly164Asp	missense	Exon 1 of 1	ENSP00000315383.5	Q53RT3-2
	ENSG00000293615	ENST00000419542.6	TSL:5	c.743G>A	p.Gly248Asp	missense	Exon 6 of 6	ENSP00000520552.1
	ENSG00000293615	ENST00000630975.4	TSL:5	c.743G>A	p.Gly248Asp	missense	Exon 7 of 7	ENSP00000520555.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	0.34	N
PhyloP100		2.4
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.80		Loss of sheet (P = 0.0357)
MVP		0.72
MPC		0.58
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.60
gMVP		0.67
Mutation Taster		=56/44	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

Other links and lift over

dbSNP: rs1435874677; hg19: chr2-70188078;