10-113876631-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_198514.4(NHLRC2):c.442G>T(p.Asp148Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (0 hom.)
• Consequence: NHLRC2 NM_198514.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.84

Genes affected

NHLRC2 (HGNC:24731): (NHL repeat containing 2) Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a domain Thioredoxin (size 157) in uniprot entity NHLC2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_198514.4
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-113876631-G-T is Pathogenic according to our data. Variant chr10-113876631-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 599377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-113876631-G-T is described in Lovd as [Pathogenic]. Variant chr10-113876631-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC2	NM_198514.4	c.442G>T	p.Asp148Tyr	missense_variant	3/11	ENST00000369301.3
NHLRC2	XM_011539769.4	c.442G>T	p.Asp148Tyr	missense_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC2	ENST00000369301.3	c.442G>T	p.Asp148Tyr	missense_variant	3/11	2	NM_198514.4	P1

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00453

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000220

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000410 AC: 103 AN: 251250 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135790

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00310

Gnomad NFE exome AF: 0.000229

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000209 AC: 306 AN: 1461538 Hom.: 0 Cov.: 31 AF XY: 0.000234 AC XY: 170 AN XY: 727090

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: 0.000232

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.000121

Gnomad4 OTH exome AF: 0.000232

GnomAD4 genome AF: 0.000433 AC: 66 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51 AN XY: 74448

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00453

Gnomad4 NFE AF: 0.000220

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.0000982

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000354 AC: 43

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2023	Published functional studies demonstrate a loss of NHLRC2 protein function in fibroblasts of patients with the D148Y variant (Uusimaa et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35255187, 29302074, 30138417, 32435055, 30239752, 34165204, 29423877, 35887114, 37179546) -

Fibrosis, neurodegeneration, and cerebral angiomatosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 21, 2023	- -
Pathogenic, criteria provided, single submitter	research	Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.77	D
MutationAssessor	Pathogenic	3.8	H
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.6	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		0.98
MPC		0.67
ClinPred		0.40	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs201701259; hg19: chr10-115636390;