5-139392684-G-T

Position:

• chr5-139392684-G-T

Variant summary

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

The NM_001161546.2(PROB1):​c.2398C>A​(p.Arg800Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000137 in 1,242,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 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)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: PROB1 NM_001161546.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.260

Genes affected

PROB1 (HGNC:41906): (proline rich basic protein 1) Located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SPATA24 (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=0.064334124).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROB1	NM_001161546.2	c.2398C>A	p.Arg800Ser	missense_variant	1/1	ENST00000434752.4	NP_001155018.1
SPATA24	XM_005271916.5	c.*3521C>A		3_prime_UTR_variant	6/6		XP_005271973.1
SPATA24	XM_011543252.3	c.*3521C>A		3_prime_UTR_variant	6/6		XP_011541554.1
SPATA24	XM_011543253.3	c.*3521C>A		3_prime_UTR_variant	6/6		XP_011541555.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PROB1	ENST00000434752.4	c.2398C>A	p.Arg800Ser	missense_variant	1/1		NM_001161546.2	ENSP00000416033	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000137 AC: 17 AN: 1242330 Hom.: 0 Cov.: 29 AF XY: 0.0000133 AC XY: 8 AN XY: 599598

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000169

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

May 24, 2024

The c.2398C>A (p.R800S) alteration is located in exon 1 (coding exon 1) of the PROB1 gene. This alteration results from a C to A substitution at nucleotide position 2398, causing the arginine (R) at amino acid position 800 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	0.19
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	12
DANN	Benign	0.72
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.047
Sift	Benign	0.24	T
Sift4G	Benign	0.68	T
Polyphen		0.22	B
Vest4		0.064
MutPred		0.33		Gain of phosphorylation at R800 (P = 0.0026);
MVP		0.030
ClinPred		0.11	T
GERP RS		1.8
Varity_R		0.072
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs960225048; hg19: chr5-138728373;