chr7-75881904-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001040456.3(RHBDD2):​c.254G>C​(p.Arg85Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R85H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHBDD2 NM_001040456.3 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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>C	p.Arg85Pro	missense	Exon 2 of 4	NP_001035546.1	Q6NTF9-1
	RHBDD2	NM_001040457.3		c.-170G>C		5_prime_UTR	Exon 3 of 5	NP_001035547.1	Q6NTF9-3
	RHBDD2	NM_001346186.2		c.-170G>C		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>C	p.Arg85Pro	missense	Exon 2 of 4	ENSP00000006777.6	Q6NTF9-1
	RHBDD2	ENST00000873334.1		c.254G>C	p.Arg85Pro	missense	Exon 2 of 4	ENSP00000543393.1
	RHBDD2	ENST00000318622.8	TSL:2	c.-170G>C		5_prime_UTR	Exon 3 of 5	ENSP00000314144.4	Q6NTF9-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.000073	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.61	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	1.0	N
REVEL	Benign	0.23
Sift	Benign	0.33	T
Sift4G	Benign	0.20	T
Polyphen		0.99	D
Vest4		0.64
MutPred		0.53		Loss of helix (P = 0.0138)
MVP		0.24
MPC		1.1
ClinPred		0.83	D
GERP RS		3.8
PromoterAI		0.0034	Neutral
Varity_R		0.18
gMVP		0.76
Mutation Taster		=55/45	polymorphism

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;