chr1-25290715-C-T

Variant names:

• chr1-25290715-C-T
• rs113982491
• NM_016124.6:c.410C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_016124.6(RHD):​c.410C>T​(p.Ala137Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00415 in 1,377,360 control chromosomes in the GnomAD database, including 966 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as no classification for the single variant (no stars).

• Frequency:
  • Genomes: 𝑓 0.021 (378 hom., cov: 20)
  • Exomes 𝑓: 0.0024 (588 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.122
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022259355).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0623 is higher than 0.05.

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.410C>T	p.Ala137Val	missense	Exon 3 of 10	NP_057208.3
	RHD	NM_001282871.2		c.410C>T	p.Ala137Val	missense	Exon 3 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.410C>T	p.Ala137Val	missense	Exon 3 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.410C>T	p.Ala137Val	missense	Exon 3 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.410C>T	p.Ala137Val	missense	Exon 3 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.410C>T	p.Ala137Val	missense	Exon 3 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes AF: 0.0205 AC: 2660 AN: 129758 Hom.: 379 Cov.: 20

Gnomad AFR AF: 0.0643

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0109

Gnomad ASJ AF: 0.00838

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000242

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00382

Gnomad NFE AF: 0.000327

Gnomad OTH AF: 0.0164

GnomAD2 exomes AF: 0.00578 AC: 1301 AN: 225064 AF XY: 0.00437

Gnomad AFR exome AF: 0.0675

Gnomad AMR exome AF: 0.00360

Gnomad ASJ exome AF: 0.00664

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000272

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00244 AC: 3048 AN: 1247484 Hom.: 588 Cov.: 31 AF XY: 0.00214 AC XY: 1331 AN XY: 622164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0694 AC: 2244 AN: 32336

American (AMR) AF: 0.00422 AC: 180 AN: 42614

Ashkenazi Jewish (ASJ) AF: 0.00635 AC: 151 AN: 23792

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39542

South Asian (SAS) AF: 0.000161 AC: 13 AN: 80528

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47058

Middle Eastern (MID) AF: 0.00324 AC: 17 AN: 5254

European-Non Finnish (NFE) AF: 0.000129 AC: 119 AN: 923112

Other (OTH) AF: 0.00607 AC: 323 AN: 53248

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0206 AC: 2670 AN: 129876 Hom.: 378 Cov.: 20 AF XY: 0.0193 AC XY: 1224 AN XY: 63408

African (AFR) AF: 0.0644 AC: 2451 AN: 38042

American (AMR) AF: 0.0109 AC: 144 AN: 13246

Ashkenazi Jewish (ASJ) AF: 0.00838 AC: 26 AN: 3104

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5094

South Asian (SAS) AF: 0.00 AC: 0 AN: 4132

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8592

Middle Eastern (MID) AF: 0.00417 AC: 1 AN: 240

European-Non Finnish (NFE) AF: 0.000327 AC: 18 AN: 54966

Other (OTH) AF: 0.0162 AC: 29 AN: 1790

Alfa AF: 0.0135 Hom.: 29

ESP6500AA AF: 0.0663 AC: 285

ESP6500EA AF: 0.000792 AC: 6

ExAC AF: 0.00647 AC: 726

Asia WGS AF: 0.00798 AC: 27 AN: 3396

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	7.2
DANN	Benign	0.71
DEOGEN2	Benign	0.0019	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.12
PrimateAI	Benign	0.31	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.025
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.22
MPC		0.085
ClinPred		0.0021	T
GERP RS		0.61
Varity_R		0.025
gMVP		0.13
Mutation Taster		=99/1	polymorphism (auto)

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: rs113982491; hg19: chr1-25617206; COSMIC: COSV59646858; COSMIC: COSV59646858;