rs33912345

chr14-60509819-C-Achr14-60509819-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007374.3(SIX6):c.421C>A(p.His141Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.563 in 1,612,972 control chromosomes in the GnomAD database, including 270,703 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.45 (19710 hom., cov: 32)
  • Exomes 𝑓: 0.57 (250993 hom.)
• Consequence: SIX6 NM_007374.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.21

Genes affected

SIX6 (HGNC:10892): (SIX homeobox 6) The protein encoded by this gene is a homeobox protein that is similar to the Drosophila 'sine oculis' gene product. This gene is found in a cluster of related genes on chromosome 14 and is thought to be involved in eye development. Defects in this gene are a cause of isolated microphthalmia with cataract type 2 (MCOPCT2). [provided by RefSeq, Jul 2008]

C14orf39 (HGNC:19849): (chromosome 14 open reading frame 39) Predicted to be involved in gamete generation and meiosis I. Predicted to be located in chromosome. Predicted to be active in central element. Implicated in primary ovarian insufficiency 18 and spermatogenic failure 52. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.372838E-6).
• BP6: Variant 14-60509819-C-A is Benign according to our data. Variant chr14-60509819-C-A is described in ClinVar as [Benign]. Clinvar id is 260163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX6	NM_007374.3	c.421C>A	p.His141Asn	missense_variant	1/2	ENST00000327720.6
C14orf39	XM_047431324.1	c.-144+5576G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX6	ENST00000327720.6	c.421C>A	p.His141Asn	missense_variant	1/2	1	NM_007374.3	P1
C14orf39	ENST00000556799.1	c.-144+5576G>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.454 AC: 69053 AN: 151962 Hom.: 19703 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.558

Gnomad AMR AF: 0.593

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.228

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.728

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.604

Gnomad OTH AF: 0.431

GnomAD3 exomes AF: 0.531 AC: 132666 AN: 249984 Hom.: 39143 AF XY: 0.530 AC XY: 71688 AN XY: 135180

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.682

Gnomad ASJ exome AF: 0.506

Gnomad EAS exome AF: 0.218

Gnomad SAS exome AF: 0.429

Gnomad FIN exome AF: 0.724

Gnomad NFE exome AF: 0.589

Gnomad OTH exome AF: 0.540

GnomAD4 exome AF: 0.575 AC: 839544 AN: 1460892 Hom.: 250993 Cov.: 62 AF XY: 0.571 AC XY: 414937 AN XY: 726586

Gnomad4 AFR exome AF: 0.0962

Gnomad4 AMR exome AF: 0.671

Gnomad4 ASJ exome AF: 0.499

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.717

Gnomad4 NFE exome AF: 0.608

Gnomad4 OTH exome AF: 0.517

GnomAD4 genome AF: 0.454 AC: 69077 AN: 152080 Hom.: 19710 Cov.: 32 AF XY: 0.460 AC XY: 34213 AN XY: 74336

Gnomad4 AFR AF: 0.115

Gnomad4 AMR AF: 0.594

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.229

Gnomad4 SAS AF: 0.419

Gnomad4 FIN AF: 0.728

Gnomad4 NFE AF: 0.604

Gnomad4 OTH AF: 0.429

Alfa AF: 0.554 Hom.: 39547

Bravo AF: 0.430

TwinsUK AF: 0.583 AC: 2160

ALSPAC AF: 0.609 AC: 2347

ESP6500AA AF: 0.117 AC: 514

ESP6500EA AF: 0.599 AC: 5151

ExAC AF: 0.514 AC: 62376

Asia WGS AF: 0.323 AC: 1126 AN: 3478

EpiCase AF: 0.576

EpiControl AF: 0.563

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 26365380, 27013732, 24875647, 25537207) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Anophthalmia-microphthalmia syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	21
Dann	Benign	0.94
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.27
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	D
MetaRNN	Benign	0.0000054	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.5	N
MutationTaster	Benign	0.0000016	P
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	1.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.55	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.14
MPC		0.96
ClinPred		0.023	T
GERP RS		5.4
Varity_R		0.25
gMVP		0.54

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: rs33912345; hg19: chr14-60976537; COSMIC: COSV59802228;