chr12-75499862-C-T

Variant names:

• chr12-75499862-C-T
• NM_007043.7:c.1093G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_007043.7(KRR1):​c.1093G>A​(p.Glu365Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: KRR1 NM_007043.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16
• Publications: 0 publications found

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]

GLIPR1 (HGNC:17001): (GLI pathogenesis related 1) This gene encodes a protein with similarity to both the pathogenesis-related protein (PR) superfamily and the cysteine-rich secretory protein (CRISP) family. Increased expression of this gene is associated with myelomocytic differentiation in macrophage and decreased expression of this gene through gene methylation is associated with prostate cancer. The protein has proapoptotic activities in prostate and bladder cancer cells. This gene is a member of a cluster on chromosome 12 containing two other similar genes. Alternatively spliced variants which encode different protein isoforms have been described; however, not all variants have been fully characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21811157).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007043.7. 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
	KRR1	NM_007043.7	MANE Select	c.1093G>A	p.Glu365Lys	missense	Exon 10 of 10	NP_008974.5
	GLIPR1	NM_006851.3	MANE Select	c.*884C>T		3_prime_UTR	Exon 6 of 6	NP_006842.2	P48060-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KRR1	ENST00000229214.9	TSL:1 MANE Select	c.1093G>A	p.Glu365Lys	missense	Exon 10 of 10	ENSP00000229214.4	Q13601-1
	KRR1	ENST00000438169.6	TSL:1	c.922G>A	p.Glu308Lys	missense	Exon 9 of 9	ENSP00000411740.2	Q13601-2
	GLIPR1	ENST00000266659.8	TSL:1 MANE Select	c.*884C>T		3_prime_UTR	Exon 6 of 6	ENSP00000266659.3	P48060-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000275 AC: 4 AN: 1455874 Hom.: 0 Cov.: 30 AF XY: 0.00000414 AC XY: 3 AN XY: 724292

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

African (AFR) AF: 0.00 AC: 0 AN: 33126

American (AMR) AF: 0.00 AC: 0 AN: 44326

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25960

East Asian (EAS) AF: 0.00 AC: 0 AN: 39324

South Asian (SAS) AF: 0.00 AC: 0 AN: 85482

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00000361 AC: 4 AN: 1109388

Other (OTH) AF: 0.00 AC: 0 AN: 60146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000782701), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.5	L
PhyloP100		2.2
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.12	N
REVEL	Benign	0.14
Sift	Uncertain	0.018	D
Sift4G	Benign	0.58	T
Polyphen		0.98	D
Vest4		0.24
MutPred		0.32		Gain of MoRF binding (P = 0.0026)
MVP		0.59
MPC		0.28
ClinPred		0.89	D
GERP RS		5.5
Varity_R		0.15
gMVP		0.15
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

hg19: chr12-75893642;