7-102467788-A-C

Variant names:

• chr7-102467788-A-C
• rs201552506
• NM_152892.3:c.643A>C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_152892.3(LRWD1):​c.643A>C​(p.Lys215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,551,014 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: LRWD1 NM_152892.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.645

Genes affected

LRWD1 (HGNC:21769): (leucine rich repeats and WD repeat domain containing 1) The protein encoded by this gene interacts with components of the origin recognition complex (ORC) and regulates the formation of the prereplicative complex. The encoded protein stabilizes the ORC and therefore aids in DNA replication. This protein is required for the G1/S phase transition of the cell cycle. In addition, the encoded protein binds to trimethylated histone H3 in heterochromatin and recruits the ORC and lysine methyltransferases, which help maintain the repressive heterochromatic state. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2015]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04355496).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LRWD1	NM_152892.3	c.643A>C	p.Lys215Gln	missense_variant	Exon 5 of 15	ENST00000292616.10	NP_690852.1
LRWD1	NM_001317721.2	c.187A>C	p.Lys63Gln	missense_variant	Exon 5 of 15		NP_001304650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LRWD1	ENST00000292616.10	c.643A>C	p.Lys215Gln	missense_variant	Exon 5 of 15	1	NM_152892.3	ENSP00000292616.5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000235

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000134 AC: 21 AN: 156490 Hom.: 0 AF XY: 0.0000727 AC XY: 6 AN XY: 82488

Gnomad AFR exome AF: 0.000114

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000177 AC: 247 AN: 1398890 Hom.: 0 Cov.: 33 AF XY: 0.000183 AC XY: 126 AN XY: 689992

Gnomad4 AFR exome AF: 0.0000316

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000216

Gnomad4 OTH exome AF: 0.000155

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152124 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74292

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000247 Hom.: 0

Bravo AF: 0.000125

ESP6500AA AF: 0.000241 AC: 1

ESP6500EA AF: 0.000245 AC: 2

ExAC AF: 0.0000434 AC: 4

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 06, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.643A>C (p.K215Q) alteration is located in exon 5 (coding exon 5) of the LRWD1 gene. This alteration results from a A to C substitution at nucleotide position 643, causing the lysine (K) at amino acid position 215 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Benign	0.65
DEOGEN2	Benign	0.0015	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.55	T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.044	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.39	N;.
REVEL	Benign	0.0080
Sift	Benign	0.19	T;.
Sift4G	Benign	0.54	T;T
Polyphen		0.028	B;.
Vest4		0.15
MVP		0.41
MPC		0.055
ClinPred		0.0087	T
GERP RS		-0.097
Varity_R		0.067
gMVP		0.28

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

LitVar

Other links and lift over

dbSNP: rs201552506; hg19: chr7-102108235;