NM_001378107.1:c.238C>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 6 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378107.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	R3HDM1	NM_001378107.1	MANE Select	c.238C>T	p.Arg80Trp	missense	Exon 5 of 27	NP_001365036.1	A0A804HIA8
	R3HDM1	NM_001282798.2		c.238C>T	p.Arg80Trp	missense	Exon 5 of 26	NP_001269727.1	Q15032-3
	R3HDM1	NM_001354200.2		c.238C>T	p.Arg80Trp	missense	Exon 5 of 26	NP_001341129.1	Q15032-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	R3HDM1	ENST00000683871.1	MANE Select	c.238C>T	p.Arg80Trp	missense	Exon 5 of 27	ENSP00000506980.1	A0A804HIA8
	R3HDM1	ENST00000264160.8	TSL:1	c.238C>T	p.Arg80Trp	missense	Exon 5 of 26	ENSP00000264160.4	Q15032-1
	R3HDM1	ENST00000409478.5	TSL:1	c.172-4802C>T		intron	N/A	ENSP00000386457.1	Q15032-2

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

African (AFR) AF: 0.00 AC: 0 AN: 33400

American (AMR) AF: 0.00 AC: 0 AN: 44214

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25972

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.00 AC: 0 AN: 85294

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53166

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1108438

Other (OTH) AF: 0.00 AC: 0 AN: 60194

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.0
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.41
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.91
MutPred		0.53		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
Mutation Taster		=74/26	polymorphism

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

Other links and lift over

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