Genetic Variant NHSL2:p.Arg77Leu (chrX-71911317-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001013627.3(NHSL2):c.230G>T(p.Arg77Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

NHSL2
NM_001013627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

Genes affected

NHSL2 (HGNC:33737): (NHS like 2) Predicted to enable calcium ion binding activity. Predicted to be involved in cell differentiation. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NHSL2 links:

ENSG00000300926 (HGNC:):

ENSG00000300926 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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=0.19363287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.230G>T	p.Arg77Leu	missense_variant	Exon 1 of 8	ENST00000633930.2	NP_001013649.2	Q5HYW2-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NHSL2	ENST00000633930.2 link	c.230G>T	p.Arg77Leu	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1	Q5HYW2-1
ENSG00000300926	ENST00000775127.1 link	n.58+603C>A		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1 link	n.235+390C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000139

AC:

AN:

71984

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000182

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1010027

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

319129

African (AFR)

AF:

0.00

AC:

AN:

23185

American (AMR)

AF:

0.00

AC:

AN:

25516

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17608

East Asian (EAS)

AF:

0.00

AC:

AN:

25362

South Asian (SAS)

AF:

0.00

AC:

AN:

46014

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24989

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3236

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

801425

Other (OTH)

AF:

0.00

AC:

AN:

42692

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.230G>T (p.R77L) alteration is located in exon 1 (coding exon 1) of the NHSL2 gene. This alteration results from a G to T substitution at nucleotide position 230, causing the arginine (R) at amino acid position 77 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_noAF

Benign

-0.11

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0094

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.47

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.19

MetaSVM

Benign

-1.1

PhyloP100

1.0

PrimateAI

Pathogenic

0.91

Sift4G

Uncertain

0.045

Vest4

0.28

MutPred

0.41

Gain of methylation at R74 (P = 0.0531);

GERP RS

3.2

PromoterAI

0.0029

Neutral

(source)

gMVP

0.16

Mutation Taster

=87/13

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over