14-60509419-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_007374.3(SIX6):c.21G>A(p.Leu7=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0289 in 1,599,486 control chromosomes in the GnomAD database, including 756 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (44 hom., cov: 33)
  • Exomes 𝑓: 0.030 (712 hom.)
• Consequence: SIX6 NM_007374.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.475

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 14-60509419-G-A is Benign according to our data. Variant chr14-60509419-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 882020.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.475 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0216 (3287/152330) while in subpopulation NFE AF= 0.0336 (2287/68022). AF 95% confidence interval is 0.0325. There are 44 homozygotes in gnomad4. There are 1573 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 3288 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX6	NM_007374.3	c.21G>A	p.Leu7=	synonymous_variant	1/2	ENST00000327720.6
C14orf39	XM_047431324.1	c.-144+5976C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX6	ENST00000327720.6	c.21G>A	p.Leu7=	synonymous_variant	1/2	1	NM_007374.3	P1
C14orf39	ENST00000556799.1	c.-144+5976C>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0216 AC: 3288 AN: 152212 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.00598

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0135

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00580

Gnomad FIN AF: 0.0385

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0336

Gnomad OTH AF: 0.0263

GnomAD3 exomes AF: 0.0201 AC: 4779 AN: 237902 Hom.: 73 AF XY: 0.0198 AC XY: 2564 AN XY: 129762

Gnomad AFR exome AF: 0.00457

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00853

Gnomad EAS exome AF: 0.0000553

Gnomad SAS exome AF: 0.00687

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0303

Gnomad OTH exome AF: 0.0244

GnomAD4 exome AF: 0.0297 AC: 42958 AN: 1447156 Hom.: 712 Cov.: 32 AF XY: 0.0289 AC XY: 20818 AN XY: 720312

Gnomad4 AFR exome AF: 0.00436

Gnomad4 AMR exome AF: 0.0128

Gnomad4 ASJ exome AF: 0.00941

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00786

Gnomad4 FIN exome AF: 0.0404

Gnomad4 NFE exome AF: 0.0342

Gnomad4 OTH exome AF: 0.0281

GnomAD4 genome AF: 0.0216 AC: 3287 AN: 152330 Hom.: 44 Cov.: 33 AF XY: 0.0211 AC XY: 1573 AN XY: 74482

Gnomad4 AFR AF: 0.00597

Gnomad4 AMR AF: 0.0135

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.0385

Gnomad4 NFE AF: 0.0336

Gnomad4 OTH AF: 0.0260

Alfa AF: 0.0288 Hom.: 10

Bravo AF: 0.0197

Asia WGS AF: 0.00462 AC: 17 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2019	This variant is associated with the following publications: (PMID: 15266624) -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Anophthalmia-microphthalmia syndrome Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
Cadd	Benign	12
Dann	Benign	0.94

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: rs61746410; hg19: chr14-60976137;