Genetic Variant C15orf39:p.Pro373Leu (chr15-75207166-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_015492.5(C15orf39):c.1118C>T(p.Pro373Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000279 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000012 ( 1 hom. )

Consequence

C15orf39
NM_015492.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.27

Variant links:

Genes affected

C15orf39 (HGNC:24497): (chromosome 15 open reading frame 39) Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

C15orf39 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.099006295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C15orf39	NM_015492.5 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 2 of 3	ENST00000394987.5	NP_056307.3	Q6ZRI6-1
C15orf39	XM_047432864.1 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 3 of 4		XP_047288820.1
C15orf39	XM_047432865.1 link	c.284C>T	p.Pro95Leu	missense_variant	Exon 4 of 5		XP_047288821.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
C15orf39	ENST00000394987.5 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 2 of 3	1	NM_015492.5	ENSP00000378438.4	Q6ZRI6-1
C15orf39	ENST00000567617.1 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 1 of 2	1		ENSP00000458025.1	Q6ZRI6-2
C15orf39	ENST00000360639.6 link	c.1118C>T	p.Pro373Leu	missense_variant	Exon 2 of 3	2		ENSP00000353854.2	Q6ZRI6-1
C15orf39	ENST00000565074.1 link	c.722C>T	p.Pro241Leu	missense_variant	Exon 1 of 1	6		ENSP00000454405.1	H3BMJ2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152114

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000628

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000239

AC:

AN:

251360

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.000299

Gnomad4 AMR exome

AF:

0.0000224

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:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.000177

AC:

AN:

152232

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.000144

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1118C>T (p.P373L) alteration is located in exon 2 (coding exon 1) of the C15orf39 gene. This alteration results from a C to T substitution at nucleotide position 1118, causing the proline (P) at amino acid position 373 to be replaced by a leucine (L). 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

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.057

T;T;.

Eigen

Benign

0.0053

Eigen_PC

Benign

-0.084

FATHMM_MKL

Benign

0.40

LIST_S2

Benign

0.82

.;T;T

M_CAP

Benign

0.072

MetaRNN

Benign

0.099

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.9

L;L;L

PROVEAN

Pathogenic

-5.7

D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

0.90

P;P;.

Vest4

0.36

MVP

0.13

MPC

0.71

ClinPred

0.63

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.37

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over