12-75506602-C-T

Variant names:

• chr12-75506602-C-T
• rs11540407
• NM_007043.7:c.401G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007043.7(KRR1):​c.401G>A​(p.Arg134Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.234 in 1,477,928 control chromosomes in the GnomAD database, including 46,544 homozygotes. 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: 𝑓 0.24 (3814 hom., cov: 25)
  • Exomes 𝑓: 0.23 (42730 hom.)
• Consequence: KRR1 NM_007043.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.30
• Publications: 28 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018532872).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.327 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KRR1	NM_007043.7	c.401G>A	p.Arg134Gln	missense_variant	Exon 4 of 10	ENST00000229214.9	NP_008974.5
KRR1	XM_047428133.1	c.107G>A	p.Arg36Gln	missense_variant	Exon 4 of 10		XP_047284089.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KRR1	ENST00000229214.9	c.401G>A	p.Arg134Gln	missense_variant	Exon 4 of 10	1	NM_007043.7	ENSP00000229214.4
KRR1	ENST00000438169.6	c.401G>A	p.Arg134Gln	missense_variant	Exon 4 of 9	1		ENSP00000411740.2
KRR1	ENST00000550023.5	n.417G>A		non_coding_transcript_exon_variant	Exon 4 of 4	2
KRR1	ENST00000550898.1	n.612G>A		non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes AF: 0.239 AC: 31765 AN: 133132 Hom.: 3810 Cov.: 25

Gnomad AFR AF: 0.210

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.120

Gnomad SAS AF: 0.341

Gnomad FIN AF: 0.178

Gnomad MID AF: 0.308

Gnomad NFE AF: 0.253

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.246 AC: 49408 AN: 201184 AF XY: 0.248

Gnomad AFR exome AF: 0.198

Gnomad AMR exome AF: 0.330

Gnomad ASJ exome AF: 0.250

Gnomad EAS exome AF: 0.109

Gnomad FIN exome AF: 0.200

Gnomad NFE exome AF: 0.245

Gnomad OTH exome AF: 0.255

GnomAD4 exome AF: 0.234 AC: 314607 AN: 1344758 Hom.: 42730 Cov.: 33 AF XY: 0.237 AC XY: 158788 AN XY: 669106

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

African (AFR) AF: 0.193 AC: 5536 AN: 28618

American (AMR) AF: 0.324 AC: 9921 AN: 30580

Ashkenazi Jewish (ASJ) AF: 0.235 AC: 5418 AN: 23012

East Asian (EAS) AF: 0.119 AC: 4591 AN: 38546

South Asian (SAS) AF: 0.312 AC: 23241 AN: 74496

European-Finnish (FIN) AF: 0.198 AC: 9561 AN: 48320

Middle Eastern (MID) AF: 0.311 AC: 1434 AN: 4616

European-Non Finnish (NFE) AF: 0.232 AC: 241781 AN: 1041152

Other (OTH) AF: 0.237 AC: 13124 AN: 55418

⚠️ 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.

GnomAD4 genome AF: 0.239 AC: 31776 AN: 133170 Hom.: 3814 Cov.: 25 AF XY: 0.238 AC XY: 15174 AN XY: 63716

African (AFR) AF: 0.209 AC: 7363 AN: 35162

American (AMR) AF: 0.291 AC: 3772 AN: 12954

Ashkenazi Jewish (ASJ) AF: 0.246 AC: 818 AN: 3328

East Asian (EAS) AF: 0.120 AC: 545 AN: 4526

South Asian (SAS) AF: 0.342 AC: 1381 AN: 4040

European-Finnish (FIN) AF: 0.178 AC: 1277 AN: 7172

Middle Eastern (MID) AF: 0.299 AC: 73 AN: 244

European-Non Finnish (NFE) AF: 0.253 AC: 15974 AN: 63144

Other (OTH) AF: 0.277 AC: 486 AN: 1752

Alfa AF: 0.248 Hom.: 13756

Bravo AF: 0.238

TwinsUK AF: 0.231 AC: 856

ALSPAC AF: 0.236 AC: 910

ESP6500AA AF: 0.203 AC: 895

ESP6500EA AF: 0.248 AC: 2131

ExAC AF: 0.254 AC: 30833

Asia WGS AF: 0.218 AC: 752 AN: 3448

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;.
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0019	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	2.9	M;M
PhyloP100		7.3
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.30
Sift	Uncertain	0.015	D;D
Sift4G	Uncertain	0.0090	D;D
Polyphen		1.0	D;.
Vest4		0.50
MPC		0.35
ClinPred		0.023	T
GERP RS		4.6
Varity_R		0.57
gMVP		0.83
Mutation Taster		=62/38	polymorphism (auto)

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: rs11540407; hg19: chr12-75900382; COSMIC: COSV56991134; COSMIC: COSV56991134;