NM_178491.4:c.91C>G

Variant names:

• chr20-44337248-C-G
• rs1432931529
• NM_178491.4:c.91C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_178491.4(R3HDML):​c.91C>G​(p.Pro31Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,728 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: R3HDML NM_178491.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.896
• 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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.028943777).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
R3HDML	NM_178491.4	c.91C>G	p.Pro31Ala	missense_variant	Exon 1 of 5	ENST00000217043.4	NP_848586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
R3HDML	ENST00000217043.4	c.91C>G	p.Pro31Ala	missense_variant	Exon 1 of 5	1	NM_178491.4	ENSP00000217043.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461728 Hom.: 0 Cov.: 36 AF XY: 0.00000275 AC XY: 2 AN XY: 727192

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111988

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.21
DANN	Benign	0.67
DEOGEN2	Benign	0.00070	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.33	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.90
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.013
Sift	Benign	0.63	T
Sift4G	Benign	0.54	T
Polyphen		0.0020	B
Vest4		0.13
MutPred		0.29		Loss of glycosylation at P31 (P = 0.0116);
MVP		0.030
MPC		0.13
ClinPred		0.038	T
GERP RS		-0.38
PromoterAI		0.0095	Neutral
Varity_R		0.023
gMVP		0.21
Mutation Taster		=98/2	polymorphism

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: rs1432931529; hg19: chr20-42965888;