6-49611163-A-G

Variant names:

• chr6-49611163-A-G
• rs75364298
• NM_000324.3:c.946-18T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000324.3(RHAG):​c.946-18T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0345 in 1,602,720 control chromosomes in the GnomAD database, including 1,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.050 (279 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1252 hom.)
• Consequence: RHAG NM_000324.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.350
• Publications: 2 publications found

Genes affected

RHAG (HGNC:10006): (Rh associated glycoprotein) The protein encoded by this gene is erythrocyte-specific and is thought to be part of a membrane channel that transports ammonium and carbon dioxide across the blood cell membrane. The encoded protein appears to interact with Rh blood group antigens and Rh30 polypeptides. Defects in this gene are a cause of regulator type Rh-null hemolytic anemia (RHN), or Rh-deficiency syndrome.[provided by RefSeq, Mar 2009]

RHAG Gene-Disease associations (from GenCC):

• Rh deficiency syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• overhydrated hereditary stomatocytosis

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 6-49611163-A-G is Benign according to our data. Variant chr6-49611163-A-G is described in ClinVar as Benign. ClinVar VariationId is 1183810.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0986 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000324.3. 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
	RHAG	NM_000324.3	MANE Select	c.946-18T>C		intron	N/A	NP_000315.2	Q02094-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHAG	ENST00000371175.10	TSL:1 MANE Select	c.946-18T>C		intron	N/A	ENSP00000360217.4	Q02094-1
	RHAG	ENST00000646272.1		c.946-18T>C		intron	N/A	ENSP00000494337.1	A0A2R8YEH1
	RHAG	ENST00000646963.1		c.946-18T>C		intron	N/A	ENSP00000495337.1	Q9UHG9

Frequencies

GnomAD3 genomes AF: 0.0499 AC: 7587 AN: 152170 Hom.: 278 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0363

Gnomad ASJ AF: 0.0501

Gnomad EAS AF: 0.0581

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0127

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0239

Gnomad OTH AF: 0.0497

GnomAD2 exomes AF: 0.0440 AC: 11035 AN: 250564 AF XY: 0.0442

Gnomad AFR exome AF: 0.101

Gnomad AMR exome AF: 0.0478

Gnomad ASJ exome AF: 0.0462

Gnomad EAS exome AF: 0.0621

Gnomad FIN exome AF: 0.0121

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0329 AC: 47767 AN: 1450432 Hom.: 1252 Cov.: 28 AF XY: 0.0344 AC XY: 24838 AN XY: 722290

African (AFR) AF: 0.102 AC: 3395 AN: 33210

American (AMR) AF: 0.0458 AC: 2046 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0460 AC: 1200 AN: 26060

East Asian (EAS) AF: 0.0506 AC: 1993 AN: 39418

South Asian (SAS) AF: 0.0969 AC: 8328 AN: 85958

European-Finnish (FIN) AF: 0.0127 AC: 680 AN: 53384

Middle Eastern (MID) AF: 0.0388 AC: 196 AN: 5054

European-Non Finnish (NFE) AF: 0.0251 AC: 27669 AN: 1102766

Other (OTH) AF: 0.0377 AC: 2260 AN: 59888

GnomAD4 genome AF: 0.0499 AC: 7601 AN: 152288 Hom.: 279 Cov.: 32 AF XY: 0.0502 AC XY: 3735 AN XY: 74470

African (AFR) AF: 0.100 AC: 4175 AN: 41558

American (AMR) AF: 0.0363 AC: 556 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0501 AC: 174 AN: 3470

East Asian (EAS) AF: 0.0584 AC: 301 AN: 5150

South Asian (SAS) AF: 0.106 AC: 513 AN: 4832

European-Finnish (FIN) AF: 0.0127 AC: 135 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0238 AC: 1621 AN: 68030

Other (OTH) AF: 0.0525 AC: 111 AN: 2116

Alfa AF: 0.0284 Hom.: 47

Bravo AF: 0.0532

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.54
DANN	Benign	0.49
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs75364298; hg19: chr6-49578876;