chr1-38919130-T-G

Position:

• chr1-38919130-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017821.5(RHBDL2):​c.83A>C​(p.Glu28Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RHBDL2 NM_017821.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.59

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06745586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RHBDL2	NM_017821.5	c.83A>C	p.Glu28Ala	missense_variant	2/8	ENST00000372990.6
LOC105378662	XR_001737994.2	n.90-44T>G		intron_variant, non_coding_transcript_variant
RHBDL2	NM_001304746.2	c.323A>C	p.Glu108Ala	missense_variant	2/8
LOC105378662	XR_947215.2	n.116-44T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RHBDL2	ENST00000372990.6	c.83A>C	p.Glu28Ala	missense_variant	2/8	5	NM_017821.5	P1
RRAGC-DT	ENST00000667635.1	n.268-45004T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The c.83A>C (p.E28A) alteration is located in exon 2 (coding exon 1) of the RHBDL2 gene. This alteration results from a A to C substitution at nucleotide position 83, causing the glutamic acid (E) at amino acid position 28 to be replaced by an alanine (A). 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	0.093
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0043	T;T;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.65	T;.;T
M_CAP	Benign	0.0048	T
MetaRNN	Benign	0.067	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.64	N;N;N
REVEL	Benign	0.075
Sift	Benign	0.43	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0080	B;B;.
Vest4		0.22
MVP		0.30
MPC		0.085
ClinPred		0.20	T
GERP RS		3.2
Varity_R		0.053
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: chr1-39384802;