10-113854873-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_198514.4(NHLRC2):c.1A>G(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NHLRC2 NM_198514.4 start_lost
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.58

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 11 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-113854873-A-G is Pathogenic according to our data. Variant chr10-113854873-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1679135.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHLRC2	NM_198514.4	c.1A>G	p.Met1?	start_lost	1/11	ENST00000369301.3
NHLRC2	XM_011539769.4	c.1A>G	p.Met1?	start_lost	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHLRC2	ENST00000369301.3	c.1A>G	p.Met1?	start_lost	1/11	2	NM_198514.4	P1
NHLRC2	ENST00000468890.1	n.50A>G		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fibrosis, neurodegeneration, and cerebral angiomatosis Pathogenic:2 Uncertain:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 20, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 25, 2022	Criteria applied: PVS1_MOD,PM2_SUP,PM3_SUP -
Likely 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
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Benign	23
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0035	T
Eigen	Benign	-0.0068
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.45	N
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.28
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.049	D
Polyphen		0.085	B
Vest4		0.84
MutPred		1.0		Loss of MoRF binding (P = 0.1863);
MVP		0.43
ClinPred		0.98	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.66
gMVP		0.48

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.

Other links and lift over

hg19: chr10-115614632;