20-44343480-G-A

Variant names:

• chr20-44343480-G-A
• rs112634290
• NM_178491.4:c.484G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_178491.4(R3HDML):​c.484G>A​(p.Asp162Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,611,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: R3HDML NM_178491.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.246
• Publications: 1 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_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.048400044).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDML	NM_178491.4	c.484G>A	p.Asp162Asn	missense_variant	Exon 3 of 5	ENST00000217043.4	NP_848586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDML	ENST00000217043.4	c.484G>A	p.Asp162Asn	missense_variant	Exon 3 of 5	1	NM_178491.4	ENSP00000217043.3
R3HDML-AS1	ENST00000735551.1	n.601-4420C>T		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.000296 AC: 45 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000205 AC: 51 AN: 248918 AF XY: 0.000245

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.000207

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000301

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000316 AC: 461 AN: 1459600 Hom.: 0 Cov.: 31 AF XY: 0.000302 AC XY: 219 AN XY: 726052

African (AFR) AF: 0.000449 AC: 15 AN: 33398

American (AMR) AF: 0.000315 AC: 14 AN: 44392

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39504

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.000375 AC: 417 AN: 1111000

Other (OTH) AF: 0.000149 AC: 9 AN: 60304

GnomAD4 genome AF: 0.000296 AC: 45 AN: 152134 Hom.: 0 Cov.: 32 AF XY: 0.000283 AC XY: 21 AN XY: 74312

African (AFR) AF: 0.000410 AC: 17 AN: 41436

American (AMR) AF: 0.000131 AC: 2 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.000214 Hom.: 0

Bravo AF: 0.000261

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000239 AC: 29

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000357

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.484G>A (p.D162N) alteration is located in exon 3 (coding exon 3) of the R3HDML gene. This alteration results from a G to A substitution at nucleotide position 484, causing the aspartic acid (D) at amino acid position 162 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	0.060
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.85
CADD	Benign	2.6
DANN	Benign	0.83
DEOGEN2	Benign	0.00031	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.048	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.82	N
PhyloP100		0.25
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.021
Sift	Benign	0.12	T
Sift4G	Benign	0.30	T
Polyphen		0.0020	B
Vest4		0.20
MVP		0.085
MPC		0.13
ClinPred		0.0079	T
GERP RS		1.4
Varity_R		0.030
gMVP		0.55
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs112634290; hg19: chr20-42972120;