Genetic Variant NHSL2:p.Asp89Glu (chrX-71911354-C-A) – 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.267C>A(p.Asp89Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,087,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.000014 ( 0 hom. 7 hem. )

Consequence

NHSL2
NM_001013627.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.553

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=0.075014204).

BS2

High Hemizygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.267C>A	p.Asp89Glu	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.267C>A	p.Asp89Glu	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1	Q5HYW2-1
ENSG00000300926	ENST00000775127.1 link	n.58+566G>T		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1 link	n.235+353G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000445

AC:

AN:

112245

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000461

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000407

AC:

AN:

49103

AF XY:

0.000119

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000167

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:

0.0000144

AC:

AN:

974942

Hom.:

Cov.:

AF XY:

0.0000233

AC XY:

AN XY:

300138

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21698

American (AMR)

AF:

0.000509

AC:

AN:

21619

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15876

East Asian (EAS)

AF:

0.00

AC:

AN:

23919

South Asian (SAS)

AF:

0.00

AC:

AN:

40675

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2865

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

783423

Other (OTH)

AF:

0.0000731

AC:

AN:

41027

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.546

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000445

AC:

AN:

112288

Hom.:

Cov.:

AF XY:

0.0000579

AC XY:

AN XY:

34528

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31039

American (AMR)

AF:

0.000461

AC:

AN:

10853

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2639

East Asian (EAS)

AF:

0.00

AC:

AN:

3466

South Asian (SAS)

AF:

0.00

AC:

AN:

2729

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6148

Middle Eastern (MID)

AF:

0.00

AC:

AN:

211

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53000

Other (OTH)

AF:

0.00

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.000200

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 21, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.267C>A (p.D89E) alteration is located in exon 1 (coding exon 1) of the NHSL2 gene. This alteration results from a C to A substitution at nucleotide position 267, causing the aspartic acid (D) at amino acid position 89 to be replaced by a glutamic acid (E). 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

0.086

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0088

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.40

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.075

MetaSVM

Benign

-1.0

PhyloP100

0.55

PrimateAI

Pathogenic

0.81

Sift4G

Benign

1.0

Vest4

0.25

MutPred

0.10

Gain of helix (P = 0.0082);

GERP RS

1.8

gMVP

0.032

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-71911354-C-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