X-71911181-G-A

Variant names:

• chrX-71911181-G-A
• rs891100037
• NM_001013627.3:c.94G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001013627.3(NHSL2):​c.94G>A​(p.Ala32Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000217 in 1,140,349 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 70 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 0.000080 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00023 (0 hom. 66 hem.)
• Consequence: NHSL2 NM_001013627.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42
• Publications: 0 publications found

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]

ENSG00000300926 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.42143613).
• BS2: High Hemizygotes in GnomAd4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.94G>A	p.Ala32Thr	missense_variant	Exon 1 of 8	ENST00000633930.2	NP_001013649.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHSL2	ENST00000633930.2	c.94G>A	p.Ala32Thr	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1
ENSG00000300926	ENST00000775127.1	n.59-468C>T		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1	n.236-468C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000796 AC: 9 AN: 113081 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000960

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000989 AC: 8 AN: 80910 AF XY: 0.000114

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: 0.000232

Gnomad OTH exome AF: 0.000391

GnomAD4 exome AF: 0.000232 AC: 238 AN: 1027268 Hom.: 0 Cov.: 30 AF XY: 0.000199 AC XY: 66 AN XY: 331368

African (AFR) AF: 0.00 AC: 0 AN: 23377

American (AMR) AF: 0.00 AC: 0 AN: 27040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18228

East Asian (EAS) AF: 0.00 AC: 0 AN: 25820

South Asian (SAS) AF: 0.00 AC: 0 AN: 48166

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3476

European-Non Finnish (NFE) AF: 0.000292 AC: 237 AN: 812176

Other (OTH) AF: 0.0000229 AC: 1 AN: 43573

GnomAD4 genome AF: 0.0000796 AC: 9 AN: 113081 Hom.: 0 Cov.: 24 AF XY: 0.000113 AC XY: 4 AN XY: 35255

African (AFR) AF: 0.0000960 AC: 3 AN: 31241

American (AMR) AF: 0.00 AC: 0 AN: 10901

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2825

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6256

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 236

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 53221

Other (OTH) AF: 0.00 AC: 0 AN: 1528

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.94G>A (p.A32T) 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 94, causing the alanine (A) at amino acid position 32 to be replaced by a threonine (T). 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	Uncertain	0.41
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.52	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.99	T
PhyloP100		2.4
PrimateAI	Pathogenic	0.86	D
Sift4G	Benign	0.39	T
Vest4		0.58
MutPred		0.37		Loss of phosphorylation at S29 (P = 0.1774);
GERP RS		4.0
PromoterAI		0.011	Neutral
gMVP		0.15

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

Other links and lift over

dbSNP: rs891100037; hg19: chrX-71131031;