17-219721-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006987.4(RPH3AL):c.629G>A(p.Ser210Asn) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 29)
• Consequence: RPH3AL NM_006987.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.88

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33146828).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPH3AL	NM_006987.4	c.629G>A	p.Ser210Asn	missense_variant	8/10	ENST00000331302.12
RPH3AL	NM_001190411.2	c.629G>A	p.Ser210Asn	missense_variant	7/9
RPH3AL	NM_001190412.2	c.542G>A	p.Ser181Asn	missense_variant	7/9
RPH3AL	NM_001190413.2	c.542G>A	p.Ser181Asn	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPH3AL	ENST00000331302.12	c.629G>A	p.Ser210Asn	missense_variant	8/10	2	NM_006987.4	P1

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 29

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

Jul 22, 2022

The c.629G>A (p.S210N) alteration is located in exon 8 (coding exon 6) of the RPH3AL gene. This alteration results from a G to A substitution at nucleotide position 629, causing the serine (S) at amino acid position 210 to be replaced by an asparagine (N). 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	Uncertain	0.43
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T;.;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.50	N
LIST_S2	Benign	0.76	T;.;.;T
M_CAP	Benign	0.0040	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.57	T
MutationAssessor	Uncertain	2.2	M;M;.;.
MutationTaster	Benign	0.70	N;N;N
PrimateAI	Uncertain	0.74	T
Sift4G	Benign	0.12	T;T;T;T
Polyphen		0.98	D;D;D;D
Vest4		0.40
MutPred		0.33		Loss of phosphorylation at S210 (P = 0.0015);Loss of phosphorylation at S210 (P = 0.0015);.;.;
MVP		0.56
MPC		0.26
ClinPred		0.90	D
GERP RS		3.5
Varity_R		0.31
gMVP		0.35

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: chr17-69512;