NM_152366.5:c.511A>C

Variant names:

• chr1-161099046-A-C
• rs11576830
• NM_152366.5:c.511A>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_152366.5(KLHDC9):​c.511A>C​(p.Ser171Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.286 in 1,595,180 control chromosomes in the GnomAD database, including 67,436 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.24 (5124 hom., cov: 32)
  • Exomes 𝑓: 0.29 (62312 hom.)
• Consequence: KLHDC9 NM_152366.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38

Genes affected

KLHDC9 (HGNC:28489): (kelch domain containing 9) Enables cyclin binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0029716194).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.351 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KLHDC9	NM_152366.5	c.511A>C	p.Ser171Arg	missense_variant	Exon 1 of 4	ENST00000368011.9	NP_689579.3
KLHDC9	NM_001007255.3	c.511A>C	p.Ser171Arg	missense_variant	Exon 1 of 4		NP_001007256.1
KLHDC9	NR_033385.2	n.425A>C		non_coding_transcript_exon_variant	Exon 2 of 5
KLHDC9	NR_033386.2	n.425A>C		non_coding_transcript_exon_variant	Exon 2 of 5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KLHDC9	ENST00000368011.9	c.511A>C	p.Ser171Arg	missense_variant	Exon 1 of 4	1	NM_152366.5	ENSP00000356990.4

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36738 AN: 152016 Hom.: 5126 Cov.: 32

Gnomad AFR AF: 0.0980

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.280

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.203

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.297

Gnomad OTH AF: 0.245

GnomAD3 exomes AF: 0.275 AC: 62139 AN: 225880 Hom.: 8876 AF XY: 0.273 AC XY: 33939 AN XY: 124352

Gnomad AFR exome AF: 0.0881

Gnomad AMR exome AF: 0.312

Gnomad ASJ exome AF: 0.277

Gnomad EAS exome AF: 0.347

Gnomad SAS exome AF: 0.204

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.292

Gnomad OTH exome AF: 0.289

GnomAD4 exome AF: 0.291 AC: 420082 AN: 1443046 Hom.: 62312 Cov.: 35 AF XY: 0.289 AC XY: 207233 AN XY: 718026

Gnomad4 AFR exome AF: 0.0858

Gnomad4 AMR exome AF: 0.309

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.388

Gnomad4 SAS exome AF: 0.206

Gnomad4 FIN exome AF: 0.305

Gnomad4 NFE exome AF: 0.301

Gnomad4 OTH exome AF: 0.277

GnomAD4 genome AF: 0.242 AC: 36750 AN: 152134 Hom.: 5124 Cov.: 32 AF XY: 0.243 AC XY: 18053 AN XY: 74360

Gnomad4 AFR AF: 0.0982

Gnomad4 AMR AF: 0.282

Gnomad4 ASJ AF: 0.280

Gnomad4 EAS AF: 0.365

Gnomad4 SAS AF: 0.203

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.297

Gnomad4 OTH AF: 0.247

Alfa AF: 0.280 Hom.: 10101

Bravo AF: 0.236

TwinsUK AF: 0.292 AC: 1081

ALSPAC AF: 0.284 AC: 1094

ESP6500AA AF: 0.0927 AC: 407

ESP6500EA AF: 0.282 AC: 2416

ExAC AF: 0.262 AC: 31660

Asia WGS AF: 0.258 AC: 897 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	4.3
DANN	Benign	0.56
DEOGEN2	Benign	0.0047	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.50	T;T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.93	N;N
REVEL	Benign	0.052
Sift	Benign	0.52	T;T
Sift4G	Benign	0.50	T;T
Polyphen		0.0	B;B
Vest4		0.17
MutPred		0.22		Gain of MoRF binding (P = 0.0164);Gain of MoRF binding (P = 0.0164);
MPC		0.34
ClinPred		0.0034	T
GERP RS		-7.1
Varity_R		0.042
gMVP		0.51

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

LitVar

Other links and lift over

dbSNP: rs11576830; hg19: chr1-161068836; COSMIC: COSV63509464; COSMIC: COSV63509464;