17-215710-T-A

Position:

• chr17-215710-T-A

Variant summary

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

The NM_006987.4(RPH3AL):​c.820A>T​(p.Thr274Ser) 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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.409

Genes affected

RPH3AL (HGNC:10296): (rabphilin 3A like (without C2 domains)) The protein encoded by this gene plays a direct regulatory role in calcium-ion-dependent exocytosis in both endocrine and exocrine cells and plays a key role in insulin secretion by pancreatic cells. This gene is likely a tumor suppressor. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jun 2010]

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=0.04643202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPH3AL	NM_006987.4	c.820A>T	p.Thr274Ser	missense_variant	9/10	ENST00000331302.12	NP_008918.1
RPH3AL	NM_001190411.2	c.820A>T	p.Thr274Ser	missense_variant	8/9		NP_001177340.1
RPH3AL	NM_001190412.2	c.733A>T	p.Thr245Ser	missense_variant	8/9		NP_001177341.1
RPH3AL	NM_001190413.2	c.733A>T	p.Thr245Ser	missense_variant	7/8		NP_001177342.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPH3AL	ENST00000331302.12	c.820A>T	p.Thr274Ser	missense_variant	9/10	2	NM_006987.4	ENSP00000328977	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

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

Sep 07, 2022

The c.820A>T (p.T274S) alteration is located in exon 9 (coding exon 7) of the RPH3AL gene. This alteration results from a A to T substitution at nucleotide position 820, causing the threonine (T) at amino acid position 274 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	0.077
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	4.2
DANN	Benign	0.81
DEOGEN2	Benign	0.038	T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.56	T;.;.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.046	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	L;L;.;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	0.29	.;.;.;N
REVEL	Benign	0.0020
Sift	Benign	0.49	.;.;.;T
Sift4G	Benign	0.73	T;T;T;T
Polyphen		0.0	B;B;B;B
Vest4		0.063
MutPred		0.27		Gain of glycosylation at T274 (P = 0.0522);Gain of glycosylation at T274 (P = 0.0522);.;.;
MVP		0.23
MPC		0.055
ClinPred		0.14	T
GERP RS		-3.6
Varity_R		0.030
gMVP		0.078

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: chr17-65501;