Genetic Variant NHSL2:p.Arg12Ser (chrX-71911121-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.34C>A(p.Arg12Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,097,023 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 8/13 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R12C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 24)

Exomes 𝑓: 0.0000030 ( 0 hom. 3 hem. )

Consequence

NHSL2
NM_001013627.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.743

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:

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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=0.14922017).

BS2

High Hemizygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3 link	c.34C>A	p.Arg12Ser	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.34C>A	p.Arg12Ser	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1	Q5HYW2-1
ENSG00000300926	ENST00000775127.1 link	n.59-408G>T		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1 link	n.236-408G>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.00000886

AC:

AN:

112838

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000305

AC:

AN:

984185

Hom.:

Cov.:

AF XY:

0.00000967

AC XY:

AN XY:

310365

show subpopulations

African (AFR)

AF:

0.0000474

AC:

AN:

21092

American (AMR)

AF:

0.00

AC:

AN:

22885

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

16121

East Asian (EAS)

AF:

0.00

AC:

AN:

23115

South Asian (SAS)

AF:

0.0000235

AC:

AN:

42640

European-Finnish (FIN)

AF:

0.0000409

AC:

AN:

24450

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2693

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

789603

Other (OTH)

AF:

0.00

AC:

AN:

41586

GnomAD4 genome

AF:

0.00000886

AC:

AN:

112838

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

35056

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31208

American (AMR)

AF:

0.00

AC:

AN:

10861

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2659

East Asian (EAS)

AF:

0.00

AC:

AN:

3532

South Asian (SAS)

AF:

0.00

AC:

AN:

2811

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6199

Middle Eastern (MID)

AF:

0.00

AC:

AN:

236

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53122

Other (OTH)

AF:

0.00

AC:

AN:

1524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.49

M_CAP

Benign

0.047

MetaRNN

Benign

0.15

MetaSVM

Benign

-1.1

PhyloP100

0.74

PrimateAI

Pathogenic

0.86

Sift4G

Benign

0.43

Vest4

0.19

MutPred

0.32

Loss of MoRF binding (P = 0.0076);

GERP RS

4.1

PromoterAI

0.018

Neutral

(source)

gMVP

0.12

Mutation Taster

=90/10

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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chrX-71911121-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over