rs146737847

chr14-60509783-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP3 BP4_Strong BP6 BS1 BS2

The NM_007374.3(SIX6):c.385G>A(p.Glu129Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0056 in 1,613,104 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0041 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (36 hom.)
• Consequence: SIX6 NM_007374.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 10.0

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 -12 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 9: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL [when FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.027642071).
• BP6: Variant 14-60509783-G-A is Benign according to our data. Variant chr14-60509783-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 445796.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00411 (626/152308) while in subpopulation NFE AF= 0.00695 (473/68020). AF 95% confidence interval is 0.00644. There are 1 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 626 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX6	NM_007374.3	c.385G>A	p.Glu129Lys	missense_variant	1/2	ENST00000327720.6
C14orf39	XM_047431324.1	c.-144+5612C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX6	ENST00000327720.6	c.385G>A	p.Glu129Lys	missense_variant	1/2	1	NM_007374.3	P1
C14orf39	ENST00000556799.1	c.-144+5612C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00411 AC: 626 AN: 152190 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00695

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00403 AC: 1011 AN: 251016 Hom.: 1 AF XY: 0.00418 AC XY: 568 AN XY: 135734

Gnomad AFR exome AF: 0.000740

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00680

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00575 AC: 8403 AN: 1460796 Hom.: 36 Cov.: 32 AF XY: 0.00569 AC XY: 4131 AN XY: 726474

Gnomad4 AFR exome AF: 0.000927

Gnomad4 AMR exome AF: 0.00170

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00173

Gnomad4 FIN exome AF: 0.00450

Gnomad4 NFE exome AF: 0.00677

Gnomad4 OTH exome AF: 0.00534

GnomAD4 genome AF: 0.00411 AC: 626 AN: 152308 Hom.: 1 Cov.: 33 AF XY: 0.00406 AC XY: 302 AN XY: 74474

Gnomad4 AFR AF: 0.00106

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00166

Gnomad4 FIN AF: 0.00377

Gnomad4 NFE AF: 0.00695

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00567 Hom.: 4

Bravo AF: 0.00370

TwinsUK AF: 0.00701 AC: 26

ALSPAC AF: 0.00856 AC: 33

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00628 AC: 54

ExAC AF: 0.00402 AC: 488

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	Reported as a risk or hypomorphic allele in relation to primary open-angle glaucoma (Carnes et al., 2014; Iglesias et al., 2014; Shah et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24150847, 28499933, 28717659, 29165578, 24875647) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -

Anophthalmia/microphthalmia-esophageal atresia syndrome;C4225424:Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Anophthalmia-microphthalmia syndrome Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

SIX6-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 24, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.028	T
MetaSVM	Uncertain	0.69	D
MutationAssessor	Pathogenic	3.1	M
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-4.0	D
REVEL	Pathogenic	0.79
Sift	Uncertain	0.020	D
Sift4G	Benign	0.064	T
Polyphen		0.97	D
Vest4		0.80
MVP		0.89
MPC		2.1
ClinPred		0.077	T
GERP RS		5.4
Varity_R		0.80
gMVP		0.60

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: rs146737847; hg19: chr14-60976501; COSMIC: COSV59802195;