chr1-25290760-A-C

Variant names:

• chr1-25290760-A-C
• rs17418085
• NM_016124.6:c.455A>C

Variant summary

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

The NM_016124.6(RHD):​c.455A>C​(p.Asn152Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0035 in 1,375,542 control chromosomes in the GnomAD database, including 817 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N152K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (305 hom., cov: 20)
  • Exomes 𝑓: 0.0019 (512 hom.)
• Consequence: RHD NM_016124.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.356
• Publications: 19 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=0.003946066).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0585 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.455A>C	p.Asn152Thr	missense	Exon 3 of 10	NP_057208.3
	RHD	NM_001282871.2		c.455A>C	p.Asn152Thr	missense	Exon 3 of 9	NP_001269800.1	Q02161-4
	RHD	NM_001282870.1		c.455A>C	p.Asn152Thr	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.455A>C	p.Asn152Thr	missense	Exon 3 of 10	ENSP00000331871.4	Q02161-1
	RHD	ENST00000342055.9	TSL:1	c.455A>C	p.Asn152Thr	missense	Exon 3 of 9	ENSP00000339577.5	Q02161-4
	RHD	ENST00000568195.5	TSL:1	c.455A>C	p.Asn152Thr	missense	Exon 3 of 9	ENSP00000456966.1	H3BT10

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2482 AN: 129258 Hom.: 305 Cov.: 20

Gnomad AFR AF: 0.0604

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00992

Gnomad ASJ AF: 0.00740

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.000723

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00385

Gnomad NFE AF: 0.000347

Gnomad OTH AF: 0.0142

GnomAD2 exomes AF: 0.00544 AC: 1224 AN: 224846 AF XY: 0.00420

Gnomad AFR exome AF: 0.0620

Gnomad AMR exome AF: 0.00339

Gnomad ASJ exome AF: 0.00621

Gnomad EAS exome AF: 0.000817

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000450

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00186 AC: 2322 AN: 1246166 Hom.: 512 Cov.: 31 AF XY: 0.00165 AC XY: 1024 AN XY: 621598

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

African (AFR) AF: 0.0497 AC: 1548 AN: 31146

American (AMR) AF: 0.00383 AC: 163 AN: 42572

Ashkenazi Jewish (ASJ) AF: 0.00560 AC: 133 AN: 23756

East Asian (EAS) AF: 0.000582 AC: 23 AN: 39532

South Asian (SAS) AF: 0.000248 AC: 20 AN: 80520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47044

Middle Eastern (MID) AF: 0.00267 AC: 14 AN: 5250

European-Non Finnish (NFE) AF: 0.000186 AC: 172 AN: 923240

Other (OTH) AF: 0.00469 AC: 249 AN: 53106

⚠️ 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: 0.0193 AC: 2493 AN: 129376 Hom.: 305 Cov.: 20 AF XY: 0.0183 AC XY: 1153 AN XY: 63166

African (AFR) AF: 0.0606 AC: 2290 AN: 37818

American (AMR) AF: 0.00990 AC: 131 AN: 13232

Ashkenazi Jewish (ASJ) AF: 0.00740 AC: 23 AN: 3110

East Asian (EAS) AF: 0.000393 AC: 2 AN: 5088

South Asian (SAS) AF: 0.000482 AC: 2 AN: 4148

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8514

Middle Eastern (MID) AF: 0.00420 AC: 1 AN: 238

European-Non Finnish (NFE) AF: 0.000347 AC: 19 AN: 54786

Other (OTH) AF: 0.0141 AC: 25 AN: 1778

Alfa AF: 0.228 Hom.: 1649

ESP6500AA AF: 0.0259 AC: 111

ESP6500EA AF: 0.00118 AC: 9

ExAC AF: 0.00649 AC: 731

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.35
DANN	Benign	0.41
DEOGEN2	Benign	0.00083	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00022	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0039	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.0	N
PhyloP100		-0.36
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.1	N
REVEL	Benign	0.030
Sift	Benign	1.0	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.11
MVP		0.19
MPC		0.087
ClinPred		0.0031	T
GERP RS		-0.42
Varity_R		0.043
gMVP		0.17
Mutation Taster		=100/0	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: rs17418085; hg19: chr1-25617251; COSMIC: COSV59645322; COSMIC: COSV59645322;