rs45549246

Positions:

• chr14-60511125-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000327720.6(SIX6):​c.614T>G​(p.Leu205Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00291 in 1,612,752 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0032 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0029 (17 hom.)
• Consequence: SIX6 ENST00000327720.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 4.75

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0074677467).
• BP6: Variant 14-60511125-T-G is Benign according to our data. Variant chr14-60511125-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 522355.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}. Variant chr14-60511125-T-G is described in Lovd as [Benign]. Variant chr14-60511125-T-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00321 (488/152192) while in subpopulation NFE AF= 0.00504 (343/67990). AF 95% confidence interval is 0.0046. There are 4 homozygotes in gnomad4. There are 235 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 488 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SIX6	NM_007374.3	c.614T>G	p.Leu205Arg	missense_variant	2/2	ENST00000327720.6	NP_031400.2
C14orf39	XM_047431324.1	c.-144+4270A>C		intron_variant			XP_047287280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SIX6	ENST00000327720.6	c.614T>G	p.Leu205Arg	missense_variant	2/2	1	NM_007374.3	ENSP00000328596	P1
C14orf39	ENST00000556799.1	c.-144+4270A>C		intron_variant		4		ENSP00000451441

Frequencies

GnomAD3 genomes AF: 0.00322 AC: 489 AN: 152074 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00481

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00504

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00312 AC: 763 AN: 244246 Hom.: 4 AF XY: 0.00334 AC XY: 446 AN XY: 133430

Gnomad AFR exome AF: 0.000530

Gnomad AMR exome AF: 0.00163

Gnomad ASJ exome AF: 0.00191

Gnomad EAS exome AF: 0.0000552

Gnomad SAS exome AF: 0.00148

Gnomad FIN exome AF: 0.00558

Gnomad NFE exome AF: 0.00452

Gnomad OTH exome AF: 0.00382

GnomAD4 exome AF: 0.00288 AC: 4209 AN: 1460560 Hom.: 17 Cov.: 32 AF XY: 0.00297 AC XY: 2158 AN XY: 726634

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.00177

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00136

Gnomad4 FIN exome AF: 0.00592

Gnomad4 NFE exome AF: 0.00308

Gnomad4 OTH exome AF: 0.00225

GnomAD4 genome AF: 0.00321 AC: 488 AN: 152192 Hom.: 4 Cov.: 33 AF XY: 0.00316 AC XY: 235 AN XY: 74406

Gnomad4 AFR AF: 0.000794

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00481

Gnomad4 NFE AF: 0.00504

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00376 Hom.: 8

Bravo AF: 0.00264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00257 AC: 22

ExAC AF: 0.00321 AC: 389

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00431

EpiControl AF: 0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	SIX6: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	This variant is associated with the following publications: (PMID: 28717659, 28499933, 24875647) -

Anophthalmia-microphthalmia syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics, Academic Medical Center

-

- -

Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Oct 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.97
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.23
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.0075	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Benign	0.81	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.060	N
REVEL	Uncertain	0.30
Sift	Benign	0.33	T
Sift4G	Benign	0.33	T
Polyphen		0.0090	B
Vest4		0.49
MVP		0.75
MPC		1.3
ClinPred		0.0094	T
GERP RS		4.1
Varity_R		0.26
gMVP		0.53

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: rs45549246; hg19: chr14-60977843;