chr1-38915647-C-T

Variant names:

• chr1-38915647-C-T
• NM_017821.5:c.310G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_017821.5(RHBDL2):​c.310G>A​(p.Gly104Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: RHBDL2 NM_017821.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.44

Genes affected

RHBDL2 (HGNC:16083): (rhomboid like 2) The protein encoded by this gene is a member of the rhomboid family of integral membrane proteins. This family contains proteins that are related to Drosophila rhomboid protein. Members of this family are found in both prokaryotes and eukaryotes and are thought to function as intramembrane serine proteases. The encoded protein is thought to release soluble growth factors by proteolytic cleavage of certain membrane-bound substrates, including ephrin B2 and ephrin B3. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2015]

RRAGC-DT (HGNC:55793): (RRAGC divergent transcript)

LOC105378662 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHBDL2	NM_017821.5	c.310G>A	p.Gly104Ser	missense_variant	Exon 3 of 8	ENST00000372990.6	NP_060291.2
RHBDL2	NM_001304746.2	c.550G>A	p.Gly184Ser	missense_variant	Exon 3 of 8		NP_001291675.1
LOC105378662	XR_001737994.2	n.89+2019C>T		intron_variant	Intron 1 of 1
LOC105378662	XR_947215.2	n.115+380C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHBDL2	ENST00000372990.6	c.310G>A	p.Gly104Ser	missense_variant	Exon 3 of 8	5	NM_017821.5	ENSP00000362081.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 13, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.310G>A (p.G104S) alteration is located in exon 3 (coding exon 2) of the RHBDL2 gene. This alteration results from a G to A substitution at nucleotide position 310, causing the glycine (G) at amino acid position 104 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0049	T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D;.;D
M_CAP	Benign	0.0098	T
MetaRNN	Uncertain	0.47	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.7	M;M;M
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.3	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.47	T;T;D
Sift4G	Benign	0.34	T;T;D
Polyphen		1.0	D;D;.
Vest4		0.65
MVP		0.51
MPC		0.11
ClinPred		0.90	D
GERP RS		4.4
Varity_R		0.19
gMVP		0.83

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-39381319;