Genetic Variant NHS:p.Ala27Ala (chrX-17375838-G-C) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_001291867.2(NHS):c.81G>C(p.Ala27Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000678 in 1,032,511 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000068 ( 0 hom. 2 hem. )

Consequence

NHS
NM_001291867.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.44

Publications

0 publications found

Variant links:

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: ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
early-onset nuclear cataract
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NHS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant X-17375838-G-C is Benign according to our data. Variant chrX-17375838-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2889344.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.44 with no splicing effect.

BS2

High AC in GnomAdExome4 at 7 XL,AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHS	NM_001291867.2 link	c.81G>C	p.Ala27Ala	synonymous_variant	Exon 1 of 9	ENST00000676302.1	NP_001278796.1	Q6T4R5-1
NHS	NM_198270.4 link	c.81G>C	p.Ala27Ala	synonymous_variant	Exon 1 of 8		NP_938011.1	Q6T4R5-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHS	ENST00000676302.1 link	c.81G>C	p.Ala27Ala	synonymous_variant	Exon 1 of 9		NM_001291867.2	ENSP00000502262.1		Q6T4R5-1
NHS	ENST00000380060.7 link	c.81G>C	p.Ala27Ala	synonymous_variant	Exon 1 of 8	1		ENSP00000369400.3		Q6T4R5-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000119

AC:

AN:

84345

AF XY:

0.00

show subpopulations

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:

0.0000320

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000678

AC:

AN:

1032511

Hom.:

Cov.:

AF XY:

0.00000596

AC XY:

AN XY:

335431

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

23883

American (AMR)

AF:

0.00

AC:

AN:

27315

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18324

East Asian (EAS)

AF:

0.00

AC:

AN:

26385

South Asian (SAS)

AF:

0.00

AC:

AN:

48873

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25523

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2821

European-Non Finnish (NFE)

AF:

0.00000736

AC:

AN:

815603

Other (OTH)

AF:

0.0000228

AC:

AN:

43784

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Nance-Horan syndrome

Benign:1

Jul 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

8.0

(source)

DANN

Benign

0.63

PhyloP100

1.4

PromoterAI

0.038

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

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

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X-17375838-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over