chrX-17727307-T-C

Variant names:

• chrX-17727307-T-C
• rs56908561
• NM_001291867.2:c.3201T>C
• NHS p.Ser1067Ser

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001291867.2(NHS):​c.3201T>C​(p.Ser1067Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,210,146 control chromosomes in the GnomAD database, including 198 homozygotes. There are 1,804 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (111 hom., 841 hem., cov: 23)
  • Exomes 𝑓: 0.0033 (87 hom. 963 hem.)
• Consequence: NHS NM_001291867.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.575
• Publications: 0 publications found

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]

NHS Gene-Disease associations (from GenCC):

• Nance-Horan syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics, G2P
• early-onset nuclear cataract

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000309710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant X-17727307-T-C is Benign according to our data. Variant chrX-17727307-T-C is described in ClinVar as Benign. ClinVar VariationId is 129774.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.575 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0887 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001291867.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	NM_001291867.2	MANE Select	c.3201T>C	p.Ser1067Ser	synonymous	Exon 7 of 9	NP_001278796.1	Q6T4R5-1
	NHS	NM_198270.4		c.3138T>C	p.Ser1046Ser	synonymous	Exon 6 of 8	NP_938011.1	Q6T4R5-2
	NHS	NM_001440780.1		c.2862T>C	p.Ser954Ser	synonymous	Exon 7 of 9	NP_001427709.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NHS	ENST00000676302.1	MANE Select	c.3201T>C	p.Ser1067Ser	synonymous	Exon 7 of 9	ENSP00000502262.1	Q6T4R5-1
	NHS	ENST00000380060.7	TSL:1	c.3138T>C	p.Ser1046Ser	synonymous	Exon 6 of 8	ENSP00000369400.3	Q6T4R5-2
	NHS	ENST00000398097.7	TSL:1	c.2670T>C	p.Ser890Ser	synonymous	Exon 7 of 9	ENSP00000381170.3	Q6T4R5-3

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 3058 AN: 112108 Hom.: 111 Cov.: 23

Gnomad AFR AF: 0.0917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0117

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0125

Gnomad NFE AF: 0.000413

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.00860 AC: 1576 AN: 183211 AF XY: 0.00585

Gnomad AFR exome AF: 0.0948

Gnomad AMR exome AF: 0.00773

Gnomad ASJ exome AF: 0.00709

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000440

Gnomad OTH exome AF: 0.00641

GnomAD4 exome AF: 0.00329 AC: 3613 AN: 1097986 Hom.: 87 Cov.: 32 AF XY: 0.00265 AC XY: 963 AN XY: 363346

African (AFR) AF: 0.0932 AC: 2459 AN: 26393

American (AMR) AF: 0.00909 AC: 320 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00722 AC: 140 AN: 19382

East Asian (EAS) AF: 0.00 AC: 0 AN: 30205

South Asian (SAS) AF: 0.000185 AC: 10 AN: 54142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40520

Middle Eastern (MID) AF: 0.00387 AC: 16 AN: 4136

European-Non Finnish (NFE) AF: 0.000339 AC: 285 AN: 841911

Other (OTH) AF: 0.00831 AC: 383 AN: 46090

GnomAD4 genome AF: 0.0273 AC: 3057 AN: 112160 Hom.: 111 Cov.: 23 AF XY: 0.0245 AC XY: 841 AN XY: 34354

African (AFR) AF: 0.0915 AC: 2816 AN: 30774

American (AMR) AF: 0.0146 AC: 155 AN: 10625

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 31 AN: 2652

East Asian (EAS) AF: 0.00 AC: 0 AN: 3587

South Asian (SAS) AF: 0.000374 AC: 1 AN: 2677

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6161

Middle Eastern (MID) AF: 0.0137 AC: 3 AN: 219

European-Non Finnish (NFE) AF: 0.000413 AC: 22 AN: 53243

Other (OTH) AF: 0.0189 AC: 29 AN: 1536

Alfa AF: 0.0327 Hom.: 564

Bravo AF: 0.0320

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	Nance-Horan syndrome (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.9
DANN	Benign	0.63
PhyloP100		0.57
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs56908561;

hg19: chrX-17745427;