rs573768953

chr2-44942452-C-T

Variant summary

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

The NM_005413.4(SIX3):c.348C>T(p.Pro116=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,597,948 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: SIX3 NM_005413.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.23

Genes affected

SIX3 (HGNC:10889): (SIX homeobox 3) This gene encodes a member of the sine oculis homeobox transcription factor family. The encoded protein plays a role in eye development. Mutations in this gene have been associated with holoprosencephaly type 2. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 2-44942452-C-T is Benign according to our data. Variant chr2-44942452-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 586592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-44942452-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00065 (99/152282) while in subpopulation NFE AF= 0.00119 (81/68000). AF 95% confidence interval is 0.000981. There are 0 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 99 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX3	NM_005413.4	c.348C>T	p.Pro116=	synonymous_variant	1/2	ENST00000260653.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX3	ENST00000260653.5	c.348C>T	p.Pro116=	synonymous_variant	1/2	1	NM_005413.4	P1

Frequencies

GnomAD3 genomes AF: 0.000651 AC: 99 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000571 AC: 130 AN: 227850 Hom.: 1 AF XY: 0.000586 AC XY: 74 AN XY: 126328

Gnomad AFR exome AF: 0.0000724

Gnomad AMR exome AF: 0.000264

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: 0.00112

Gnomad OTH exome AF: 0.000347

GnomAD4 exome AF: 0.00124 AC: 1798 AN: 1445666 Hom.: 4 Cov.: 33 AF XY: 0.00121 AC XY: 869 AN XY: 719602

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000269

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000369

Gnomad4 NFE exome AF: 0.00156

Gnomad4 OTH exome AF: 0.000664

GnomAD4 genome AF: 0.000650 AC: 99 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74442

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000726 Hom.: 0

Bravo AF: 0.000737

EpiCase AF: 0.00147

EpiControl AF: 0.00125

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 26, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	SIX3: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Holoprosencephaly 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
Cadd	Benign	12
Dann	Benign	0.89

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: rs573768953; hg19: chr2-45169591;