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14-60509238-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.08
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]
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]

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ACMG classification

Classification made for transcript

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/exons MANE UniProt
SIX6NM_007374.3 linkuse as main transcriptc.-161T>C 5_prime_UTR_variant 1/2 ENST00000327720.6
C14orf39XM_047431324.1 linkuse as main transcriptc.-144+6157A>G intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SIX6ENST00000327720.6 linkuse as main transcriptc.-161T>C 5_prime_UTR_variant 1/21 NM_007374.3 P1
C14orf39ENST00000556799.1 linkuse as main transcriptc.-144+6157A>G intron_variant 4

Frequencies

GnomAD3 genomes
AF:
0.872
AC:
132542
AN:
151996
Hom.:
58281
Cov.:
32
show subpopulations
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
show subpopulations
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
show subpopulations
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:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJun 26, 2018- -
Anophthalmia-microphthalmia syndrome Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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

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

Other links and lift over

dbSNP: rs1956558; hg19: chr14-60975956; API