15-89477590-G-A

Variant names:

• chr15-89477590-G-A
• rs1596402766
• NM_016321.3:c.1039C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_016321.3(RHCG):​c.1039C>T​(p.Pro347Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RHCG NM_016321.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86
• Publications: 0 publications found

Genes affected

RHCG (HGNC:18140): (Rh family C glycoprotein) Enables ammonium transmembrane transporter activity; ankyrin binding activity; and identical protein binding activity. Involved in ammonium transmembrane transport; cellular ion homeostasis; and transepithelial ammonium transport. Located in apical plasma membrane and basolateral plasma membrane. Is integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016321.3. 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
	RHCG	NM_016321.3	MANE Select	c.1039C>T	p.Pro347Ser	missense	Exon 7 of 11	NP_057405.1	Q9UBD6
	RHCG	NM_001321041.2		c.1039C>T	p.Pro347Ser	missense	Exon 7 of 11	NP_001307970.1	Q9UBD6
	RHCG	NR_110261.2		n.1015-13C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHCG	ENST00000268122.9	TSL:1 MANE Select	c.1039C>T	p.Pro347Ser	missense	Exon 7 of 11	ENSP00000268122.4	Q9UBD6
	RHCG	ENST00000560081.5	TSL:1	n.976-13C>T		intron	N/A	ENSP00000453588.1	H0YMF8
	RHCG	ENST00000909204.1		c.1066C>T	p.Pro356Ser	missense	Exon 7 of 11	ENSP00000579263.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

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: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

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	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.29	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Benign	0.053	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Pathogenic	3.6	H
PhyloP100		9.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-7.6	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Gain of glycosylation at P347 (P = 0.0047)
MVP		0.43
MPC		0.81
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.88
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.38		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.38		Position offset: -13

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1596402766; hg19: chr15-90020821;