10-98208270-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001351015.2(R3HCC1L):c.156A>C(p.Lys52Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: R3HCC1L NM_001351015.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.167

Genes affected

R3HCC1L (HGNC:23512): (R3H domain and coiled-coil containing 1 like) Colocalizes with exon-exon junction complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08506489).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
R3HCC1L	NM_001351015.2	c.156A>C	p.Lys52Asn	missense_variant	5/10	ENST00000298999.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
R3HCC1L	ENST00000298999.8	c.156A>C	p.Lys52Asn	missense_variant	5/10	5	NM_001351015.2	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250758 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135628

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461838 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2023

The c.156A>C (p.K52N) alteration is located in exon 4 (coding exon 1) of the R3HCC1L gene. This alteration results from a A to C substitution at nucleotide position 156, causing the lysine (K) at amino acid position 52 to be replaced by an asparagine (N). 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	0.21
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	16
Dann	Uncertain	0.99
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.22	N
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.085	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.3	N;N;.;.
REVEL	Benign	0.084
Sift	Uncertain	0.0030	D;D;.;.
Sift4G	Benign	0.091	T;T;T;T
Polyphen		0.96	.;.;D;.
Vest4		0.13
MutPred		0.19		Loss of methylation at K52 (P = 0.0026);Loss of methylation at K52 (P = 0.0026);Loss of methylation at K52 (P = 0.0026);Loss of methylation at K52 (P = 0.0026);
MVP		0.34
MPC		0.12
ClinPred		0.25	T
GERP RS		0.61
Varity_R		0.035
gMVP		0.021

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: rs772223175; hg19: chr10-99968027;