X-71911104-G-T

Variant names:

• chrX-71911104-G-T
• rs750531794
• NM_001013627.3:c.17G>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.59
• 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 -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	c.17G>T	p.Arg6Leu	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.17G>T	p.Arg6Leu	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1
ENSG00000300926	ENST00000775127.1	n.59-391C>A		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1	n.236-391C>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.000195 AC: 22 AN: 112863 Hom.: 0 Cov.: 23

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: 6 AN: 21863 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: 0.000755

Gnomad NFE exome AF: 0.000675

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000299 AC: 279 AN: 932525 Hom.: 0 Cov.: 29 AF XY: 0.000273 AC XY: 79 AN XY: 289517

African (AFR) AF: 0.000101 AC: 2 AN: 19713

American (AMR) AF: 0.00 AC: 0 AN: 14566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13965

East Asian (EAS) AF: 0.00 AC: 0 AN: 21319

South Asian (SAS) AF: 0.00 AC: 0 AN: 35244

European-Finnish (FIN) AF: 0.000612 AC: 14 AN: 22880

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2472

European-Non Finnish (NFE) AF: 0.000335 AC: 256 AN: 763284

Other (OTH) AF: 0.000179 AC: 7 AN: 39082

GnomAD4 genome AF: 0.000195 AC: 22 AN: 112863 Hom.: 0 Cov.: 23 AF XY: 0.000199 AC XY: 7 AN XY: 35099

African (AFR) AF: 0.0000961 AC: 3 AN: 31205

American (AMR) AF: 0.00 AC: 0 AN: 10852

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3527

South Asian (SAS) AF: 0.00 AC: 0 AN: 2816

European-Finnish (FIN) AF: 0.000161 AC: 1 AN: 6204

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000339 AC: 18 AN: 53159

Other (OTH) AF: 0.00 AC: 0 AN: 1524

Alfa AF: 0.000214 Hom.: 1

Bravo AF: 0.000193

ExAC AF: 0.0000869 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.029	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.80	T
PhyloP100		1.6
PrimateAI	Pathogenic	0.86	D
Sift4G	Pathogenic	0.0	D
Vest4		0.34
MutPred		0.65		Loss of disorder (P = 0.013);
GERP RS		4.1
PromoterAI		0.061	Neutral
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

Other links and lift over

dbSNP: rs750531794; hg19: chrX-71130954;