NM_000324.3:c.1068-26T>C

Variant names:

• chr6-49607246-A-G
• rs375376615
• NM_000324.3:c.1068-26T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000324.3(RHAG):​c.1068-26T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,596,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.00066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000067 (0 hom.)
• Consequence: RHAG NM_000324.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.940
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 5 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000663 (101/152342) while in subpopulation AFR AF = 0.00236 (98/41590). AF 95% confidence interval is 0.00198. There are 0 homozygotes in GnomAd4. There are 40 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1068-26T>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.1068-26T>C		intron	N/A	ENSP00000360217.4	Q02094-1
	RHAG	ENST00000646272.1		c.1068-26T>C		intron	N/A	ENSP00000494337.1	A0A2R8YEH1
	RHAG	ENST00000646963.1		c.1068-26T>C		intron	N/A	ENSP00000495337.1	Q9UHG9

Frequencies

GnomAD3 genomes AF: 0.000663 AC: 101 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000219 AC: 53 AN: 242410 AF XY: 0.000153

Gnomad AFR exome AF: 0.00329

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000183

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000672 AC: 97 AN: 1443694 Hom.: 0 Cov.: 27 AF XY: 0.0000543 AC XY: 39 AN XY: 718658

African (AFR) AF: 0.00260 AC: 86 AN: 33128

American (AMR) AF: 0.00 AC: 0 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25882

East Asian (EAS) AF: 0.00 AC: 0 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 84870

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.00000638 AC: 7 AN: 1097538

Other (OTH) AF: 0.0000669 AC: 4 AN: 59784

GnomAD4 genome AF: 0.000663 AC: 101 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.000537 AC XY: 40 AN XY: 74496

African (AFR) AF: 0.00236 AC: 98 AN: 41590

American (AMR) AF: 0.000131 AC: 2 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000759

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.76
PhyloP100		-0.94
BranchPoint Hunter		5.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs375376615; hg19: chr6-49574959;