Genetic Variant NM_001013627.3:c.17G>T (chrX-71911104-G-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001013627.3(NHSL2):c.17G>T(p.Arg6Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000288 in 1,045,388 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 86 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., 7 hem., cov: 23)

Exomes 𝑓: 0.00030 ( 0 hom. 79 hem. )

Consequence

NHSL2
NM_001013627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2299206).

BS2

High Hemizygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.17G>T	p.Arg6Leu	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.17G>T	p.Arg6Leu	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1	Q5HYW2-1
ENSG00000300926	ENST00000775127.1 link	n.59-391C>A		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1 link	n.236-391C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.000195

AC:

AN:

112863

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000961

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000161

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000339

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000274

AC:

AN:

21863

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:

0.00

Gnomad FIN exome

AF:

0.000755

Gnomad NFE exome

AF:

0.000675

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000299

AC:

279

AN:

932525

Hom.:

Cov.:

AF XY:

0.000273

AC XY:

AN XY:

289517

show subpopulations

African (AFR)

AF:

0.000101

AC:

AN:

19713

American (AMR)

AF:

0.00

AC:

AN:

14566

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13965

East Asian (EAS)

AF:

0.00

AC:

AN:

21319

South Asian (SAS)

AF:

0.00

AC:

AN:

35244

European-Finnish (FIN)

AF:

0.000612

AC:

AN:

22880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2472

European-Non Finnish (NFE)

AF:

0.000335

AC:

256

AN:

763284

Other (OTH)

AF:

0.000179

AC:

AN:

39082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000195

AC:

AN:

112863

Hom.:

Cov.:

AF XY:

0.000199

AC XY:

AN XY:

35099

show subpopulations

African (AFR)

AF:

0.0000961

AC:

AN:

31205

American (AMR)

AF:

0.00

AC:

AN:

10852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3527

South Asian (SAS)

AF:

0.00

AC:

AN:

2816

European-Finnish (FIN)

AF:

0.000161

AC:

AN:

6204

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000339

AC:

AN:

53159

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000193

ExAC

AF:

0.0000869

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 31, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.17G>T (p.R6L) 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 17, causing the arginine (R) at amino acid position 6 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

Pathogenic

0.82

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.029

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.61

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.80

PhyloP100

1.6

PrimateAI

Pathogenic

0.86

Sift4G

Pathogenic

0.0

Vest4

0.34

MutPred

0.65

Loss of disorder (P = 0.013);

GERP RS

4.1

PromoterAI

0.061

Neutral

(source)

gMVP

0.60

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_001013627.3:c.17G>T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over