rs1956558

Variant names:

• chr14-60509238-T-C
• rs1956558
• NM_007374.3:c.-161T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_007374.3(SIX6):​c.-161T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.889 in 663,008 control chromosomes in the GnomAD database, including 263,589 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58339 hom., cov: 32)
  • Exomes 𝑓: 0.89 (205250 hom.)
• Consequence: SIX6 NM_007374.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.08

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 14-60509238-T-C is Benign according to our data. Variant chr14-60509238-T-C is described in ClinVar as [Benign]. Clinvar id is 313426.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.914 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX6	NM_007374.3	c.-161T>C		5_prime_UTR_variant	Exon 1 of 2	ENST00000327720.6	NP_031400.2
C14orf39	XM_047431324.1	c.-144+6157A>G		intron_variant	Intron 1 of 18		XP_047287280.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX6	ENST00000327720	c.-161T>C		5_prime_UTR_variant	Exon 1 of 2	1	NM_007374.3	ENSP00000328596.5
C14orf39	ENST00000556799.1	c.-144+6157A>G		intron_variant	Intron 1 of 5	4		ENSP00000451441.1

Frequencies

GnomAD3 genomes AF: 0.872 AC: 132542 AN: 151996 Hom.: 58281 Cov.: 32

Gnomad AFR AF: 0.765

Gnomad AMI AF: 0.946

Gnomad AMR AF: 0.907

Gnomad ASJ AF: 0.900

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.738

Gnomad FIN AF: 0.974

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.920

Gnomad OTH AF: 0.872

GnomAD4 exome AF: 0.894 AC: 456753 AN: 510894 Hom.: 205250 Cov.: 6 AF XY: 0.886 AC XY: 239855 AN XY: 270578

Gnomad4 AFR exome AF: 0.757

Gnomad4 AMR exome AF: 0.921

Gnomad4 ASJ exome AF: 0.895

Gnomad4 EAS exome AF: 0.855

Gnomad4 SAS exome AF: 0.751

Gnomad4 FIN exome AF: 0.973

Gnomad4 NFE exome AF: 0.919

Gnomad4 OTH exome AF: 0.890

GnomAD4 genome AF: 0.872 AC: 132665 AN: 152114 Hom.: 58339 Cov.: 32 AF XY: 0.874 AC XY: 64956 AN XY: 74352

Gnomad4 AFR AF: 0.765

Gnomad4 AMR AF: 0.907

Gnomad4 ASJ AF: 0.900

Gnomad4 EAS AF: 0.876

Gnomad4 SAS AF: 0.740

Gnomad4 FIN AF: 0.974

Gnomad4 NFE AF: 0.920

Gnomad4 OTH AF: 0.873

Alfa AF: 0.906 Hom.: 10423

Bravo AF: 0.865

Asia WGS AF: 0.820 AC: 2847 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 26, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Anophthalmia-microphthalmia syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	9.4
DANN	Benign	0.46

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: rs1956558; hg19: chr14-60975956;