rs143065064

Positions:

• chrX-17635577-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000398097.7(NHS):​c.11C>T​(p.Ala4Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,165,554 control chromosomes in the GnomAD database, including 14 homozygotes. There are 2,062 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0043 (1 hom., 160 hem., cov: 23)
  • Exomes 𝑓: 0.0057 (13 hom. 1902 hem.)
• Consequence: NHS ENST00000398097.7 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.24

Genes affected

NHS (HGNC:7820): (NHS actin remodeling regulator) This gene encodes a protein containing four conserved nuclear localization signals. The encoded protein functions in eye, tooth, craniofacial and brain development, and it can regulate actin remodeling and cell morphology. Mutations in this gene have been shown to cause Nance-Horan syndrome, and also X-linked cataract-40. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, May 2014]

LOC105373142 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005512178).
• BP6: Variant X-17635577-C-T is Benign according to our data. Variant chrX-17635577-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-17635577-C-T is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd4 at 160 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NHS	NM_001291867.2	c.566-52165C>T		intron_variant		ENST00000676302.1	NP_001278796.1
LOC105373142	XR_007068402.1	n.1822G>A		non_coding_transcript_exon_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000398097.7	c.11C>T	p.Ala4Val	missense_variant	1/9	1		ENSP00000381170
NHS	ENST00000617601.4	c.-8C>T		5_prime_UTR_variant	1/8	1		ENSP00000478433
NHS	ENST00000676302.1	c.566-52165C>T		intron_variant			NM_001291867.2	ENSP00000502262	P4
NHS	ENST00000380060.7	c.566-52165C>T		intron_variant		1		ENSP00000369400	A2

Frequencies

GnomAD3 genomes AF: 0.00433 AC: 487 AN: 112511 Hom.: 1 Cov.: 23 AF XY: 0.00464 AC XY: 161 AN XY: 34663

Gnomad AFR AF: 0.000775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00270

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000366

Gnomad FIN AF: 0.00581

Gnomad MID AF: 0.0167

Gnomad NFE AF: 0.00644

Gnomad OTH AF: 0.00266

GnomAD3 exomes AF: 0.00441 AC: 492 AN: 111471 Hom.: 1 AF XY: 0.00468 AC XY: 184 AN XY: 39287

Gnomad AFR exome AF: 0.000475

Gnomad AMR exome AF: 0.00176

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000358

Gnomad FIN exome AF: 0.00629

Gnomad NFE exome AF: 0.00683

Gnomad OTH exome AF: 0.00503

GnomAD4 exome AF: 0.00574 AC: 6040 AN: 1052990 Hom.: 13 Cov.: 30 AF XY: 0.00553 AC XY: 1902 AN XY: 343876

Gnomad4 AFR exome AF: 0.000522

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000624

Gnomad4 FIN exome AF: 0.00782

Gnomad4 NFE exome AF: 0.00633

Gnomad4 OTH exome AF: 0.00530

GnomAD4 genome AF: 0.00432 AC: 486 AN: 112564 Hom.: 1 Cov.: 23 AF XY: 0.00461 AC XY: 160 AN XY: 34726

Gnomad4 AFR AF: 0.000773

Gnomad4 AMR AF: 0.00270

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000368

Gnomad4 FIN AF: 0.00581

Gnomad4 NFE AF: 0.00645

Gnomad4 OTH AF: 0.00263

Alfa AF: 0.00671 Hom.: 288

Bravo AF: 0.00363

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00312 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00669 AC: 16

ExAC AF: 0.00373 AC: 91

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	18
DANN	Uncertain	1.0
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.0055	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	0.70	N
REVEL	Benign	0.024
Sift	Benign	0.15	T
Sift4G	Benign	0.070	T
Vest4		0.042
MVP		0.69
ClinPred		0.010	T
GERP RS		4.2

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

LitVar

Other links and lift over

dbSNP: rs143065064; hg19: chrX-17653697;