2-135616692-C-T

Variant names:

• chr2-135616692-C-T
• rs1157007126
• NM_001378107.1:c.238C>T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001378107.1(R3HDM1):​c.238C>T​(p.Arg80Trp) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,456,046 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: R3HDM1 NM_001378107.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.03

Genes affected

R3HDM1 (HGNC:9757): (R3H domain containing 1) Enables RNA binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.844

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDM1	NM_001378107.1	c.238C>T	p.Arg80Trp	missense_variant	Exon 5 of 27	ENST00000683871.1	NP_001365036.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDM1	ENST00000683871.1	c.238C>T	p.Arg80Trp	missense_variant	Exon 5 of 27		NM_001378107.1	ENSP00000506980.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1456046 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724036

Gnomad4 AFR exome AF: 0.00

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 04, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.238C>T (p.R80W) alteration is located in exon 5 (coding exon 3) of the R3HDM1 gene. This alteration results from a C to T substitution at nucleotide position 238, causing the arginine (R) at amino acid position 80 to be replaced by a tryptophan (W). 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	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;.
Vest4		0.91
MutPred		0.53		Gain of catalytic residue at L78 (P = 0.0032);Gain of catalytic residue at L78 (P = 0.0032);
MVP		0.74
MPC		0.90
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.77
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: -24

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1157007126; hg19: chr2-136374262; COSMIC: COSV51520454; COSMIC: COSV51520454;