Genetic Variant NHSL2:p.Arg64His (chrX-71911278-G-A) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001013627.3(NHSL2):c.191G>A(p.Arg64His) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,026,710 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 5 hem. )

Consequence

NHSL2
NM_001013627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.02

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: Likely_benign. The variant received -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.191G>A	p.Arg64His	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.191G>A	p.Arg64His	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1	Q5HYW2-1
ENSG00000300926	ENST00000775127.1 link	n.59-565C>T		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1 link	n.235+429C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

82813

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000107

AC:

AN:

1026710

Hom.:

Cov.:

AF XY:

0.0000152

AC XY:

AN XY:

329900

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23868

American (AMR)

AF:

0.00

AC:

AN:

27169

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18216

East Asian (EAS)

AF:

0.00

AC:

AN:

26082

South Asian (SAS)

AF:

0.00

AC:

AN:

47963

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3540

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

811020

Other (OTH)

AF:

0.0000460

AC:

AN:

43484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Feb 14, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.191G>A (p.R64H) alteration is located in exon 1 (coding exon 1) of the NHSL2 gene. This alteration results from a G to A substitution at nucleotide position 191, causing the arginine (R) at amino acid position 64 to be replaced by a histidine (H). 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

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.26

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.032

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.65

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.60

MetaSVM

Benign

-0.68

PhyloP100

6.0

PrimateAI

Pathogenic

0.91

Sift4G

Pathogenic

0.0

Vest4

0.49

MutPred

0.59

Loss of phosphorylation at S67 (P = 0.0553);

GERP RS

4.3

PromoterAI

0.027

Neutral

(source)

gMVP

0.30

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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X-71911278-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over