chr13-39038682-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001012754.4(NHLRC3):​c.43C>T​(p.Leu15Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000681 in 1,614,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NHLRC3
NM_001012754.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0750
Variant links:
Genes affected
NHLRC3 (HGNC:33751): (NHL repeat containing 3) This gene encodes a protein containing NCL-1, HT2A and Lin-41 (NHL) family repeats. Mammalian NHL-repeat containing proteins may be involved in a variety of enzymatic processes, including protein modification through ubiquitination. Alternatively spliced transcript variants have been observed for this gene. [provided by RefSeq, Aug 2012]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.04320681).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NHLRC3NM_001012754.4 linkc.43C>T p.Leu15Phe missense_variant Exon 1 of 7 ENST00000379600.8 NP_001012772.1 Q5JS37-1Q68DP7
NHLRC3NM_001017370.3 linkc.43C>T p.Leu15Phe missense_variant Exon 1 of 6 NP_001017370.1 Q5JS37-2Q68DP7
NHLRC3NR_073109.1 linkn.155+217C>T intron_variant Intron 1 of 6

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NHLRC3ENST00000379600.8 linkc.43C>T p.Leu15Phe missense_variant Exon 1 of 7 1 NM_001012754.4 ENSP00000368920.3 Q5JS37-1
NHLRC3ENST00000379599.6 linkc.43C>T p.Leu15Phe missense_variant Exon 1 of 6 1 ENSP00000368919.2 Q5JS37-2
NHLRC3ENST00000470258.5 linkc.-508+217C>T intron_variant Intron 1 of 6 1 ENSP00000418127.1 C9J973
NHLRC3ENST00000473371.1 linkn.377C>T non_coding_transcript_exon_variant Exon 1 of 2 2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152180
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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:
0.0000159
AC:
4
AN:
251494
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135920
show subpopulations
Gnomad AFR exome
AF:
0.000185
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:
0.00000879
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461884
Hom.:
0
Cov.:
30
AF XY:
0.00000275
AC XY:
2
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152298
Hom.:
0
Cov.:
32
AF XY:
0.0000537
AC XY:
4
AN XY:
74452
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.0000653
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:
0.0000111
Hom.:
0
Bravo
AF:
0.0000378
ExAC
AF:
0.0000330
AC:
4
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 19, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.43C>T (p.L15F) alteration is located in exon 1 (coding exon 1) of the NHLRC3 gene. This alteration results from a C to T substitution at nucleotide position 43, causing the leucine (L) at amino acid position 15 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
0.071
BayesDel_addAF
Benign
-0.33
T
BayesDel_noAF
Benign
-0.43
CADD
Benign
14
DANN
Benign
0.95
DEOGEN2
Benign
0.0048
T;.
Eigen
Benign
-0.77
Eigen_PC
Benign
-0.81
FATHMM_MKL
Benign
0.053
N
LIST_S2
Benign
0.67
T;T
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.043
T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.81
L;L
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.56
N;N
REVEL
Benign
0.032
Sift
Benign
0.12
T;T
Sift4G
Uncertain
0.016
D;D
Polyphen
0.0020
B;.
Vest4
0.21
MVP
0.54
MPC
0.082
ClinPred
0.047
T
GERP RS
2.3
Varity_R
0.037
gMVP
0.23

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.060
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.

Other links and lift over

dbSNP: rs139618208; hg19: chr13-39612819; API