chrX-71911121-C-T

Variant names:

• chrX-71911121-C-T
• rs756078762
• NM_001013627.3:c.34C>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.34C>T​(p.Arg12Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000994 in 1,097,065 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 30 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., 1 hem., cov: 24)
  • Exomes 𝑓: 0.00010 (0 hom. 29 hem.)
• Consequence: NHSL2 NM_001013627.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.743
• 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=0.11679137).
• BS2: High Hemizygotes in GnomAdExome4 at 29 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHSL2	NM_001013627.3	c.34C>T	p.Arg12Cys	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.34C>T	p.Arg12Cys	missense_variant	Exon 1 of 8	5	NM_001013627.3	ENSP00000488668.1
ENSG00000300926	ENST00000775127.1	n.59-408G>A		intron_variant	Intron 1 of 2
ENSG00000300926	ENST00000775128.1	n.236-408G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.0000798 AC: 9 AN: 112836 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000641

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000143 AC: 7 AN: 48837 AF XY: 0.000184

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000152

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000233

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000102 AC: 100 AN: 984182 Hom.: 0 Cov.: 29 AF XY: 0.0000934 AC XY: 29 AN XY: 310362

African (AFR) AF: 0.0000474 AC: 1 AN: 21092

American (AMR) AF: 0.0000874 AC: 2 AN: 22885

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16121

East Asian (EAS) AF: 0.00 AC: 0 AN: 23115

South Asian (SAS) AF: 0.000117 AC: 5 AN: 42637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2693

European-Non Finnish (NFE) AF: 0.000111 AC: 88 AN: 789603

Other (OTH) AF: 0.0000962 AC: 4 AN: 41586

GnomAD4 genome AF: 0.0000797 AC: 9 AN: 112883 Hom.: 0 Cov.: 24 AF XY: 0.0000285 AC XY: 1 AN XY: 35113

African (AFR) AF: 0.0000640 AC: 2 AN: 31271

American (AMR) AF: 0.00 AC: 0 AN: 10874

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2659

East Asian (EAS) AF: 0.00 AC: 0 AN: 3519

South Asian (SAS) AF: 0.00 AC: 0 AN: 2803

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6199

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 214

European-Non Finnish (NFE) AF: 0.000132 AC: 7 AN: 53114

Other (OTH) AF: 0.00 AC: 0 AN: 1544

Alfa AF: 0.0000883 Hom.: 1

Bravo AF: 0.0000529

ExAC AF: 0.000154 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 14, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.34C>T (p.R12C) alteration is located in exon 1 (coding exon 1) of the NHSL2 gene. This alteration results from a C to T substitution at nucleotide position 34, causing the arginine (R) at amino acid position 12 to be replaced by a cysteine (C). 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	0.23
BayesDel_noAF	Pathogenic	0.24
CADD	Uncertain	24
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.012	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
PhyloP100		0.74
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.035	D
Vest4		0.14
MutPred		0.34		Loss of MoRF binding (P = 9e-04);
GERP RS		4.1
PromoterAI		0.036	Neutral
gMVP		0.099

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: rs756078762; hg19: chrX-71130971;