rs139508538

Variant names:

• chr1-25301000-C-G
• rs139508538
• NM_016124.6:c.541C>G

Your query was ambiguous. Multiple possible variants found:

• chr1-25301000-C-G
• chr1-25301000-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP3 BS2_Supporting

The NM_016124.6(RHD):​c.541C>G​(p.Leu181Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,246,826 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000014 (5 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0100
• Publications: 1 publications found

Genes affected

RHD (HGNC:10009): (Rh blood group D antigen) The Rh blood group system is the second most clinically significant of the blood groups, second only to ABO. It is also the most polymorphic of the blood groups, with variations due to deletions, gene conversions, and missense mutations. The Rh blood group includes this gene, which encodes the RhD protein, and a second gene that encodes both the RhC and RhE antigens on a single polypeptide. The two genes, and a third unrelated gene, are found in a cluster on chromosome 1. The classification of Rh-positive and Rh-negative individuals is determined by the presence or absence of the highly immunogenic RhD protein on the surface of erythrocytes. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RSRP1 (HGNC:25234): (arginine and serine rich protein 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.83
• BS2: High Homozygotes in GnomAdExome4 at 5 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016124.6. 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
	RHD	NM_016124.6	MANE Select	c.541C>G	p.Leu181Val	missense	Exon 4 of 10	NP_057208.3
	RHD	NM_001282871.2		c.541C>G	p.Leu181Val	missense	Exon 4 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.541C>G	p.Leu181Val	missense	Exon 4 of 9	NP_001269799.1	Q5XLT0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHD	ENST00000328664.9	TSL:1 MANE Select	c.541C>G	p.Leu181Val	missense	Exon 4 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.541C>G	p.Leu181Val	missense	Exon 4 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.541C>G	p.Leu181Val	missense	Exon 4 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD2 exomes AF: 0.0000356 AC: 8 AN: 224836 AF XY: 0.0000330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000605

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000136 AC: 17 AN: 1246826 Hom.: 5 Cov.: 31 AF XY: 0.0000161 AC XY: 10 AN XY: 621842

African (AFR) AF: 0.00 AC: 0 AN: 31952

American (AMR) AF: 0.000117 AC: 5 AN: 42616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23788

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 80552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47032

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5252

European-Non Finnish (NFE) AF: 0.0000130 AC: 12 AN: 922904

Other (OTH) AF: 0.00 AC: 0 AN: 53194

GnomAD4 genome Cov.: 21

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000894 AC: 1

ClinVar

ClinVar submissions as Germline

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	Benign	0.11
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	10
DANN	Uncertain	0.99
DEOGEN2	Benign	0.095	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.013	T
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		-0.010
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.20
Sift	Benign	0.047	D
Sift4G	Benign	0.088	T
Polyphen		0.030	B
Vest4		0.35
MutPred		0.85		Gain of catalytic residue at L181 (P = 0.0178)
MVP		0.34
MPC		0.13
ClinPred		0.17	T
GERP RS		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.090
gMVP		0.65
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: rs139508538; hg19: chr1-25627491;