Genetic Variant C15orf61:p.Thr49Ile (chr15-67521394-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001143936.2(C15orf61):c.146C>T(p.Thr49Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000935 in 1,389,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000094 ( 0 hom. )

Consequence

C15orf61
NM_001143936.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.26

Variant links:

Genes affected

C15orf61 (HGNC:34453): (chromosome 15 open reading frame 61) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

C15orf61 links:

IQCH-AS1 (HGNC:44104): (IQCH antisense RNA 1)

IQCH-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
C15orf61	NM_001143936.2 link	c.146C>T	p.Thr49Ile	missense_variant	Exon 1 of 2	ENST00000342683.6	NP_001137408.1	A6NNL5
IQCH-AS1	NR_040051.1 link	n.299+152G>A		intron_variant	Intron 1 of 5
IQCH-AS1	NR_040052.1 link	n.326+125G>A		intron_variant	Intron 1 of 5
IQCH-AS1	NR_040054.1 link	n.351+100G>A		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
C15orf61	ENST00000342683.6 link	c.146C>T	p.Thr49Ile	missense_variant	Exon 1 of 2	1	NM_001143936.2	ENSP00000342254.4		A6NNL5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000622

AC:

AN:

144758

Hom.:

AF XY:

0.0000383

AC XY:

AN XY:

78294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000326

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:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000935

AC:

AN:

1389734

Hom.:

Cov.:

AF XY:

0.00000729

AC XY:

AN XY:

685828

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000308

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:

0.00000185

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 26, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146C>T (p.T49I) alteration is located in exon 1 (coding exon 1) of the C15orf61 gene. This alteration results from a C to T substitution at nucleotide position 146, causing the threonine (T) at amino acid position 49 to be replaced by an isoleucine (I). 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

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.38

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.81

MetaSVM

Uncertain

0.0012

MutationAssessor

Uncertain

2.5

PROVEAN

Pathogenic

-5.4

REVEL

Uncertain

0.61

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.82

MutPred

0.42

Gain of sheet (P = 0.0149);

MVP

0.21

ClinPred

0.86

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.92

gMVP

0.83

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