chr14-60509419-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_007374.3(SIX6):c.21G>A(p.Leu7Leu) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.475

Variant links:

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]

SIX6 links:

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]

C14orf39 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 3287 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX6	NM_007374.3 link	c.21G>A	p.Leu7Leu	synonymous_variant	Exon 1 of 2	ENST00000327720.6	NP_031400.2	O95475Q6P051
C14orf39	XM_047431324.1 link	c.-144+5976C>T		intron_variant	Intron 1 of 18		XP_047287280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX6	ENST00000327720.6 link	c.21G>A	p.Leu7Leu	synonymous_variant	Exon 1 of 2	1	NM_007374.3	ENSP00000328596.5		O95475
C14orf39	ENST00000556799.1 link	c.-144+5976C>T		intron_variant	Intron 1 of 5	4		ENSP00000451441.1		G3V3U9

Frequencies

GnomAD3 genomes

AF:

0.0216

AC:

3288

AN:

152212

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0198

AC XY:

2564

AN XY:

129762

show subpopulations

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.:

AF XY:

0.0289

AC XY:

20818

AN XY:

720312

show subpopulations

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.:

Cov.:

AF XY:

0.0211

AC XY:

1573

AN XY:

74482

show subpopulations

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.:

Bravo

AF:

0.0197

Asia WGS

AF:

0.00462

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 15266624) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Anophthalmia-microphthalmia syndrome

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over