dbSNP rs186016810: NHLRC3:p.Pro107Arg (chr13-39039646-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001012754.4(NHLRC3):c.320C>G(p.Pro107Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. P107L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NHLRC3
NM_001012754.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.74

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]

NHLRC3 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.875

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHLRC3	NM_001012754.4 link	c.320C>G	p.Pro107Arg	missense_variant	Exon 3 of 7	ENST00000379600.8	NP_001012772.1	Q5JS37-1Q68DP7
NHLRC3	NM_001017370.3 link	c.320C>G	p.Pro107Arg	missense_variant	Exon 3 of 6		NP_001017370.1	Q5JS37-2Q68DP7
NHLRC3	NR_073109.1 link	n.391C>G		non_coding_transcript_exon_variant	Exon 3 of 7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NHLRC3	ENST00000379600.8 link	c.320C>G	p.Pro107Arg	missense_variant	Exon 3 of 7	1	NM_001012754.4	ENSP00000368920.3	Q5JS37-1
NHLRC3	ENST00000379599.6 link	c.320C>G	p.Pro107Arg	missense_variant	Exon 3 of 6	1		ENSP00000368919.2	Q5JS37-2
NHLRC3	ENST00000470258 link	c.-272C>G		5_prime_UTR_variant	Exon 3 of 7	1		ENSP00000418127.1	C9J973
NHLRC3	ENST00000473371.1 link	n.1066C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1459998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726456

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

T;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.91

D;D

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.87

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.4

M;M

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-5.5

D;D

REVEL

Pathogenic

0.89

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.0070

D;T

Polyphen

1.0

D;.

Vest4

0.75

MutPred

0.72

Gain of catalytic residue at F111 (P = 0.001);Gain of catalytic residue at F111 (P = 0.001);

MVP

0.98

MPC

0.44

ClinPred

1.0

GERP RS

5.4

Varity_R

0.62

gMVP

0.91

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over