Genetic Variant KNOP1:p.Arg430Arg (chr16-19706999-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001012991.3(KNOP1):c.1288C>A(p.Arg430Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,688 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

KNOP1
NM_001012991.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.40

Publications

0 publications found

Variant links:

Genes affected

KNOP1 (HGNC:34404): (lysine rich nucleolar protein 1) The protein encoded by this gene is a nucleolar protein that interacts with zinc finger 106 protein. The encoded protein has several of the same characteristics as nucleostemin and may be involved in testis development. [provided by RefSeq, Feb 2017]

KNOP1 links:

ENSG00000261312 (HGNC:):

ENSG00000261312 links:

VPS35L (HGNC:24641): (VPS35 endosomal protein sorting factor like) Involved in Golgi to plasma membrane transport and endocytic recycling. Located in endosome. Implicated in Ritscher-Schinzel syndrome. [provided by Alliance of Genome Resources, Apr 2022]

VPS35L Gene-Disease associations (from GenCC):

Ritscher-Schinzel syndrome
Inheritance: AR Classification: LIMITED Submitted by: Franklin by Genoox
Ritscher-Schinzel syndrome 3
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

VPS35L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP7

Synonymous conserved (PhyloP=1.4 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012991.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNOP1	NM_001012991.3	MANE Select	c.1288C>A	p.Arg430Arg	synonymous	Exon 5 of 5	NP_001013009.2	Q1ED39
KNOP1	NM_001348527.2		c.1468C>A	p.Arg490Arg	synonymous	Exon 5 of 5	NP_001335456.1
KNOP1	NM_001348528.2		c.1288C>A	p.Arg430Arg	synonymous	Exon 6 of 6	NP_001335457.1	Q1ED39

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KNOP1	ENST00000219837.12	TSL:1 MANE Select	c.1288C>A	p.Arg430Arg	synonymous	Exon 5 of 5	ENSP00000219837.7	Q1ED39
KNOP1	ENST00000858467.1		c.1288C>A	p.Arg430Arg	synonymous	Exon 5 of 5	ENSP00000528526.1
KNOP1	ENST00000858468.1		c.1288C>A	p.Arg430Arg	synonymous	Exon 6 of 6	ENSP00000528527.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461688

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86238

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53408

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5636

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112004

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over