8-23291500-C-A

Position:

• chr8-23291500-C-A

Variant summary

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

The NM_001136108.3(R3HCC1):​c.992C>A​(p.Thr331Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,399,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: R3HCC1 NM_001136108.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.68

Genes affected

R3HCC1 (HGNC:27329): (R3H domain and coiled-coil containing 1) Predicted to enable nucleic acid binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
R3HCC1	NM_001136108.3	c.992C>A	p.Thr331Lys	missense_variant	5/8	ENST00000265806.12	NP_001129580.2
R3HCC1	NM_001301650.2	c.866C>A	p.Thr289Lys	missense_variant	6/9		NP_001288579.1
R3HCC1	NR_125897.1	n.961C>A		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
R3HCC1	ENST00000265806.12	c.992C>A	p.Thr331Lys	missense_variant	5/8	1	NM_001136108.3	ENSP00000265806	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399086 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 AN XY: 690052

Gnomad4 AFR exome AF: 0.0000317

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Jul 20, 2022

The c.431C>A (p.T144K) alteration is located in exon 5 (coding exon 2) of the R3HCC1 gene. This alteration results from a C to A substitution at nucleotide position 431, causing the threonine (T) at amino acid position 144 to be replaced by a lysine (K). 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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.;.;.
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.56	D;D;D;D
MetaSVM	Benign	-0.55	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.0	.;.;D;D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	.;.;D;D
Sift4G	Benign	0.076	T;T;T;T
Vest4		0.83
MutPred		0.41		.;.;Gain of ubiquitination at T371 (P = 0.017);.;
MVP		0.23
ClinPred		1.0	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.87

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-23149013;