5-139392998-T-A

Position:

• chr5-139392998-T-A

Variant summary

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

The NM_001161546.2(PROB1):​c.2084A>T​(p.Tyr695Phe) 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: 33)
• Consequence: PROB1 NM_001161546.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.78

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 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=0.30535173).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PROB1	NM_001161546.2	c.2084A>T	p.Tyr695Phe	missense_variant	1/1	ENST00000434752.4	NP_001155018.1
SPATA24	XM_005271916.5	c.*3207A>T		3_prime_UTR_variant	6/6		XP_005271973.1
SPATA24	XM_011543252.3	c.*3207A>T		3_prime_UTR_variant	6/6		XP_011541554.1
SPATA24	XM_011543253.3	c.*3207A>T		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.2084A>T	p.Tyr695Phe	missense_variant	1/1		NM_001161546.2	ENSP00000416033	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Dec 28, 2023

The c.2084A>T (p.Y695F) alteration is located in exon 1 (coding exon 1) of the PROB1 gene. This alteration results from a A to T substitution at nucleotide position 2084, causing the tyrosine (Y) at amino acid position 695 to be replaced by a phenylalanine (F). 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	0.22
BayesDel_addAF	Uncertain	0.033	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	0.97	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.64	T
Polyphen		1.0	D
Vest4		0.47
MutPred		0.24		Loss of phosphorylation at Y695 (P = 0.0115);
MVP		0.055
ClinPred		0.88	D
GERP RS		4.8
Varity_R		0.37
gMVP		0.050

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: rs746858794; hg19: chr5-138728687;