6-49606843-A-G

Position:

• chr6-49606843-A-G

Variant summary

Our verdict is Benign. Variant got -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 donor 5th base, 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_donor_5th_base, intron
• Scores: Splicing: ADA: 0.001651
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.500

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR,BG gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RHAG	NM_000324.3	c.1212+5T>C		splice_donor_5th_base_variant, intron_variant		ENST00000371175.10	NP_000315.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RHAG	ENST00000371175.10	c.1212+5T>C		splice_donor_5th_base_variant, intron_variant		1	NM_000324.3	ENSP00000360217	P2
RHAG	ENST00000646272.1	c.1217T>C	p.Leu406Pro	missense_variant	9/10			ENSP00000494337	A2
RHAG	ENST00000646939.1	c.*34+5T>C		splice_donor_5th_base_variant, intron_variant				ENSP00000494709
RHAG	ENST00000646963.1	c.1138+307T>C		intron_variant				ENSP00000495337

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

GnomAD3 exomes AF: 0.00104 AC: 261 AN: 250582 Hom.: 1 AF XY: 0.000989 AC XY: 134 AN XY: 135422

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 SAS 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

Gnomad4 AFR exome AF: 0.0000609

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00748

Gnomad4 NFE exome AF: 0.000492

Gnomad4 OTH exome AF: 0.000422

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00781

Gnomad4 NFE AF: 0.00106

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000881 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

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 30, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	RHAG: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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
MutationTaster	Benign	1.0	N;N
GERP RS		2.6

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

Publications

LitVar

Other links and lift over

dbSNP: rs200975172; hg19: chr6-49574556;