dbSNP rs11540407: KRR1:p.Arg134Leu (chr12-75506602-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_007043.7(KRR1):c.401G>T(p.Arg134Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,397,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 25)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KRR1
NM_007043.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.30

Publications

0 publications found

Variant links:

Genes affected

KRR1 (HGNC:5176): (KRR1 small subunit processome component homolog) Enables RNA binding activity. Predicted to be involved in rRNA processing. Located in chromosome; intercellular bridge; and nuclear lumen. [provided by Alliance of Genome Resources, Apr 2022]

KRR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRR1	NM_007043.7 link	c.401G>T	p.Arg134Leu	missense_variant	Exon 4 of 10	ENST00000229214.9	NP_008974.5	Q13601-1
KRR1	XM_047428133.1 link	c.107G>T	p.Arg36Leu	missense_variant	Exon 4 of 10		XP_047284089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KRR1	ENST00000229214.9 link	c.401G>T	p.Arg134Leu	missense_variant	Exon 4 of 10	1	NM_007043.7	ENSP00000229214.4	Q13601-1
KRR1	ENST00000438169.6 link	c.401G>T	p.Arg134Leu	missense_variant	Exon 4 of 9	1		ENSP00000411740.2	Q13601-2
KRR1	ENST00000550023.5 link	n.417G>T		non_coding_transcript_exon_variant	Exon 4 of 4	2
KRR1	ENST00000550898.1 link	n.612G>T		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134630

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1397266

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693480

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

29604

American (AMR)

AF:

0.00

AC:

AN:

31230

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23450

East Asian (EAS)

AF:

0.00

AC:

AN:

39010

South Asian (SAS)

AF:

0.00

AC:

AN:

76674

European-Finnish (FIN)

AF:

0.0000205

AC:

AN:

48794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1086300

Other (OTH)

AF:

0.00

AC:

AN:

57436

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

134630

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

64432

African (AFR)

AF:

0.00

AC:

AN:

35508

American (AMR)

AF:

0.00

AC:

AN:

13162

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3348

East Asian (EAS)

AF:

0.00

AC:

AN:

4574

South Asian (SAS)

AF:

0.00

AC:

AN:

4112

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7316

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

63714

Other (OTH)

AF:

0.00

AC:

AN:

1770

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.051

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Uncertain

-0.26

MutationAssessor

Uncertain

2.2

M;M

PhyloP100

7.3

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-5.8

D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.82

P;.

Vest4

0.89

MutPred

0.46

Loss of MoRF binding (P = 0.1061);Loss of MoRF binding (P = 0.1061);

MVP

0.63

MPC

0.16

ClinPred

1.0

GERP RS

4.6

Varity_R

0.79

gMVP

0.90

Mutation Taster

=9/91

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over