rs200975172

Variant names:

• chr6-49606843-A-G
• rs200975172
• NM_000324.3:c.1212+5T>C

Your query was ambiguous. Multiple possible variants found:

• chr6-49606843-A-G
• chr6-49606843-A-C
• chr6-49606843-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000324.3(RHAG):​c.1212+5T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000708 in 1,581,584 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (3 hom.)
• Consequence: RHAG NM_000324.3 splice_region, intron
• Scores: Splicing: ADA: 0.001651
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.500
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005898595).
• BP6: Variant 6-49606843-A-G is Benign according to our data. Variant chr6-49606843-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 2727778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00104 (158/152194) while in subpopulation NFE AF = 0.00106 (72/68042). AF 95% confidence interval is 0.000861. There are 0 homozygotes in GnomAd4. There are 100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.1212+5T>C		splice_region 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.1212+5T>C		splice_region intron	N/A	ENSP00000360217.4	Q02094-1
	RHAG	ENST00000646272.1		c.1217T>C	p.Leu406Pro	missense	Exon 9 of 10	ENSP00000494337.1	A0A2R8YEH1
	RHAG	ENST00000646963.1		c.1138+307T>C		intron	N/A	ENSP00000495337.1	Q9UHG9

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 158 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00781

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00106

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00104 AC: 261 AN: 250582 AF XY: 0.000989

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00717

Gnomad NFE exome AF: 0.000901

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000672 AC: 961 AN: 1429390 Hom.: 3 Cov.: 27 AF XY: 0.000679 AC XY: 484 AN XY: 713264

African (AFR) AF: 0.0000609 AC: 2 AN: 32856

American (AMR) AF: 0.0000224 AC: 1 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 85572

European-Finnish (FIN) AF: 0.00748 AC: 399 AN: 53362

Middle Eastern (MID) AF: 0.000175 AC: 1 AN: 5722

European-Non Finnish (NFE) AF: 0.000492 AC: 533 AN: 1082518

Other (OTH) AF: 0.000422 AC: 25 AN: 59258

GnomAD4 genome AF: 0.00104 AC: 158 AN: 152194 Hom.: 0 Cov.: 33 AF XY: 0.00135 AC XY: 100 AN XY: 74346

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.000196 AC: 3 AN: 15278

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00781 AC: 83 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00106 AC: 72 AN: 68042

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.000389

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000857 AC: 104

EpiCase AF: 0.000764

EpiControl AF: 0.000534

ClinVar

ClinVar submissions

Significance: Benign/Likely 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
AlphaMissense	Benign	0.046
BayesDel_noAF	Benign	-0.71
CADD	Benign	11
DANN	Benign	0.80
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0059	T
PhyloP100		-0.50
GERP RS		2.6
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0017
dbscSNV1_RF	Benign	0.070
SpliceAI score (max)		0.090		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: rs200975172; hg19: chr6-49574556;