chr20-44341199-T-C

Variant names:

• chr20-44341199-T-C
• rs754876787
• NM_178491.4:c.265T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_178491.4(R3HDML):​c.265T>C​(p.Trp89Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,459,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: R3HDML NM_178491.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.66
• Publications: 0 publications found

Genes affected

R3HDML (HGNC:16249): (R3H domain containing like) Predicted to enable peptidase inhibitor activity. Predicted to be involved in negative regulation of peptidase activity. Predicted to be active in extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

R3HDML-AS1 (HGNC:55830): (R3HDML antisense RNA 1)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.956

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDML	NM_178491.4	c.265T>C	p.Trp89Arg	missense_variant	Exon 2 of 5	ENST00000217043.4	NP_848586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDML	ENST00000217043.4	c.265T>C	p.Trp89Arg	missense_variant	Exon 2 of 5	1	NM_178491.4	ENSP00000217043.3
R3HDML-AS1	ENST00000735551.1	n.601-2139A>G		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000801 AC: 2 AN: 249544 AF XY: 0.00000741

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1459394 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 725728

African (AFR) AF: 0.00 AC: 0 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86074

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53390

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1110402

Other (OTH) AF: 0.0000166 AC: 1 AN: 60262

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Pathogenic	4.3	H
PhyloP100		5.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-13	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.80
MutPred		0.84		Gain of disorder (P = 0.0329);
MVP		0.39
MPC		0.80
ClinPred		0.96	D
GERP RS		4.4
Varity_R		0.72
gMVP		0.93
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs754876787; hg19: chr20-42969839;