17-32294328-G-A

Variant names:

• chr17-32294328-G-A
• rs765563126
• NM_138328.3:c.554G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_138328.3(RHBDL3):​c.554G>A​(p.Gly185Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,836 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RHBDL3 NM_138328.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.90
• Publications: 0 publications found

Genes affected

RHBDL3 (HGNC:16502): (rhomboid like 3) Predicted to enable serine-type endopeptidase activity. Predicted to be involved in proteolysis. Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.097135186).
• BP6: Variant 17-32294328-G-A is Benign according to our data. Variant chr17-32294328-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3314190.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138328.3. 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
	RHBDL3	NM_138328.3	MANE Select	c.554G>A	p.Gly185Asp	missense	Exon 5 of 9	NP_612201.1	P58872-1
	RHBDL3	NM_001363835.1		c.554G>A	p.Gly185Asp	missense	Exon 5 of 8	NP_001350764.1
	RHBDL3	NM_001330181.2		c.530G>A	p.Gly177Asp	missense	Exon 4 of 8	NP_001317110.1	P58872-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHBDL3	ENST00000269051.9	TSL:1 MANE Select	c.554G>A	p.Gly185Asp	missense	Exon 5 of 9	ENSP00000269051.4	P58872-1
	RHBDL3	ENST00000431505.6	TSL:1	c.554G>A	p.Gly185Asp	missense	Exon 5 of 8	ENSP00000394849.2	A4FU16
	RHBDL3	ENST00000538145.5	TSL:1	c.530G>A	p.Gly177Asp	missense	Exon 4 of 8	ENSP00000442092.1	P58872-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251430 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461836 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727216

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111976

Other (OTH) AF: 0.00 AC: 0 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00233887), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	9.2
DANN	Benign	0.49
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.44	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.097	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.57	N
PhyloP100		2.9
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.12	T
Sift4G	Benign	0.90	T
Polyphen		0.0	B
Vest4		0.24
MutPred		0.40		Gain of solvent accessibility (P = 0.0648)
MVP		0.73
MPC		0.31
ClinPred		0.075	T
GERP RS		-1.1
Varity_R		0.049
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs765563126; hg19: chr17-30621347;