rs11547498

Variant names:

• chr7-75881904-G-A
• rs11547498
• NM_001040456.3:c.254G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-75881904-G-A
• chr7-75881904-G-C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001040456.3(RHBDD2):​c.254G>A​(p.Arg85His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000328 in 1,614,168 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00025 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (1 hom.)
• Consequence: RHBDD2 NM_001040456.3 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 2.72
• Publications: 8 publications found

Genes affected

RHBDD2 (HGNC:23082): (rhomboid domain containing 2) The protein encoded by this gene is a member of the rhomboid family of membrane-bound proteases and is overexpressed in some breast cancers. Members of this family are involved in intramembrane proteolysis. In mouse, the orthologous protein associates with the Golgi body. [provided by RefSeq, Sep 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008404404).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040456.3. 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
	RHBDD2	NM_001040456.3	MANE Select	c.254G>A	p.Arg85His	missense	Exon 2 of 4	NP_001035546.1	Q6NTF9-1
	RHBDD2	NM_001040457.3		c.-170G>A		5_prime_UTR	Exon 3 of 5	NP_001035547.1	Q6NTF9-3
	RHBDD2	NM_001346186.2		c.-170G>A		5_prime_UTR	Exon 4 of 6	NP_001333115.1	Q6NTF9-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDD2	ENST00000006777.11	TSL:1 MANE Select	c.254G>A	p.Arg85His	missense	Exon 2 of 4	ENSP00000006777.6	Q6NTF9-1
	RHBDD2	ENST00000873334.1		c.254G>A	p.Arg85His	missense	Exon 2 of 4	ENSP00000543393.1
	RHBDD2	ENST00000318622.8	TSL:2	c.-170G>A		5_prime_UTR	Exon 3 of 5	ENSP00000314144.4	Q6NTF9-3

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152168 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00559

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000385 AC: 96 AN: 249526 AF XY: 0.000392

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00445

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000336 AC: 491 AN: 1461882 Hom.: 1 Cov.: 32 AF XY: 0.000363 AC XY: 264 AN XY: 727240

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000459 AC: 12 AN: 26134

East Asian (EAS) AF: 0.0103 AC: 408 AN: 39698

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000432 AC: 48 AN: 1112004

Other (OTH) AF: 0.000232 AC: 14 AN: 60396

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152286 Hom.: 1 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74480

African (AFR) AF: 0.00 AC: 0 AN: 41568

American (AMR) AF: 0.00 AC: 0 AN: 15290

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

East Asian (EAS) AF: 0.00561 AC: 29 AN: 5172

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68024

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

Alfa AF: 0.000317 Hom.: 1

Bravo AF: 0.000181

ExAC AF: 0.000446 AC: 54

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0084	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.15	N
REVEL	Benign	0.049
Sift	Benign	0.54	T
Sift4G	Benign	0.55	T
Polyphen		0.031	B
Vest4		0.20
MVP		0.12
MPC		1.1
ClinPred		0.047	T
GERP RS		3.8
PromoterAI		0.0033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.047
gMVP		0.28
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11547498; hg19: chr7-75511222;