Genetic Variant SIX6:p.Ile6Ile (chr14-60509416-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_007374.3(SIX6):c.18C>T(p.Ile6Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,599,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. I6I) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00099 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

SIX6
NM_007374.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.247

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 14-60509416-C-T is Benign according to our data. Variant chr14-60509416-C-T is described in ClinVar as [Benign]. Clinvar id is 772058.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=0.247 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000991 (151/152366) while in subpopulation AFR AF= 0.00351 (146/41592). AF 95% confidence interval is 0.00305. There are 0 homozygotes in gnomad4. There are 81 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 151 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX6	NM_007374.3 link	c.18C>T	p.Ile6Ile	synonymous_variant	Exon 1 of 2	ENST00000327720.6	NP_031400.2	O95475Q6P051
C14orf39	XM_047431324.1 link	c.-144+5979G>A		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.18C>T	p.Ile6Ile	synonymous_variant	Exon 1 of 2	1	NM_007374.3	ENSP00000328596.5		O95475
C14orf39	ENST00000556799.1 link	c.-144+5979G>A		intron_variant	Intron 1 of 5	4		ENSP00000451441.1		G3V3U9

Frequencies

GnomAD3 genomes

AF:

0.000992

AC:

151

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00352

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000252

AC:

AN:

237894

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

129766

show subpopulations

Gnomad AFR exome

AF:

0.00328

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000897

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.000116

AC:

168

AN:

1447194

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

720328

show subpopulations

Gnomad4 AFR exome

AF:

0.00424

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.000991

AC:

151

AN:

152366

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74504

show subpopulations

Gnomad4 AFR

AF:

0.00351

Gnomad4 AMR

AF:

0.000326

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.00120

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

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