13-39038682-C-A

Variant names:

• chr13-39038682-C-A
• rs139618208
• NM_001012754.4:c.43C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001012754.4(NHLRC3):​c.43C>A​(p.Leu15Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,180 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L15F) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NHLRC3 NM_001012754.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0750
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1393477).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012754.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC3	NM_001012754.4	MANE Select	c.43C>A	p.Leu15Ile	missense	Exon 1 of 7	NP_001012772.1	Q5JS37-1
	NHLRC3	NM_001017370.3		c.43C>A	p.Leu15Ile	missense	Exon 1 of 6	NP_001017370.1	Q5JS37-2
	NHLRC3	NR_073109.1		n.155+217C>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHLRC3	ENST00000379600.8	TSL:1 MANE Select	c.43C>A	p.Leu15Ile	missense	Exon 1 of 7	ENSP00000368920.3	Q5JS37-1
	NHLRC3	ENST00000379599.6	TSL:1	c.43C>A	p.Leu15Ile	missense	Exon 1 of 6	ENSP00000368919.2	Q5JS37-2
	NHLRC3	ENST00000470258.5	TSL:1	c.-508+217C>A		intron	N/A	ENSP00000418127.1	C9J973

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74324

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.90
DEOGEN2	Benign	0.0062	T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.075
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.035
Sift	Benign	0.033	D
Sift4G	Benign	0.27	T
Polyphen		0.0080	B
Vest4		0.19
MutPred		0.59		Gain of catalytic residue at G10 (P = 0)
MVP		0.67
MPC		0.080
ClinPred		0.11	T
GERP RS		2.3
PromoterAI		-0.066	Neutral
Varity_R		0.056
gMVP		0.16
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs139618208; hg19: chr13-39612819;