10-113858573-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_198514.4(NHLRC2):c.224A>T(p.Asp75Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,488 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 Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NHLRC2 NM_198514.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.81

Genes affected

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.778
• PP5: Variant 10-113858573-A-T is Pathogenic according to our data. Variant chr10-113858573-A-T is described in ClinVar as [Pathogenic]. Clinvar id is 1279930.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC2	NM_198514.4	c.224A>T	p.Asp75Val	missense_variant	2/11	ENST00000369301.3
NHLRC2	XM_011539769.4	c.224A>T	p.Asp75Val	missense_variant	2/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC2	ENST00000369301.3	c.224A>T	p.Asp75Val	missense_variant	2/11	2	NM_198514.4	P1
NHLRC2	ENST00000468890.1	n.273A>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457488 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725388

Gnomad4 AFR exome AF: 0.0000300

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.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fibrosis, neurodegeneration, and cerebral angiomatosis Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	28
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.78	D
MetaSVM	Benign	-0.60	T
MutationAssessor	Uncertain	2.8	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.1	D
REVEL	Uncertain	0.40
Sift	Benign	0.099	T
Sift4G	Benign	0.17	T
Polyphen		0.99	D
Vest4		0.74
MutPred		0.61		Gain of methylation at K74 (P = 0.0258);
MVP		0.78
MPC		0.32
ClinPred		0.98	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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.

Other links and lift over

hg19: chr10-115618332;