2-44942197-TAGCGGCGGCGGGAACGGTGCGGGAGGCGGCGGCGGCGCGGGAGGCGGC-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_005413.4(SIX3):c.126_173del(p.Gly43_Gly58del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000796 in 150,694 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S32S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000080 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000056 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SIX3 NM_005413.4 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.80

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 Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_005413.4.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX3	NM_005413.4	c.126_173del	p.Gly43_Gly58del	inframe_deletion	1/2	ENST00000260653.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX3	ENST00000260653.5	c.126_173del	p.Gly43_Gly58del	inframe_deletion	1/2	1	NM_005413.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000797 AC: 12 AN: 150586 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000976

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000727 AC: 17 AN: 233984 Hom.: 0 AF XY: 0.0000780 AC XY: 10 AN XY: 128160

Gnomad AFR exome AF: 0.0000663

Gnomad AMR exome AF: 0.000146

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.000164

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000561 AC: 81 AN: 1443648 Hom.: 0 AF XY: 0.0000529 AC XY: 38 AN XY: 718644

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000135

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.000105

Gnomad4 FIN exome AF: 0.0000256

Gnomad4 NFE exome AF: 0.0000487

Gnomad4 OTH exome AF: 0.0000333

GnomAD4 genome AF: 0.0000796 AC: 12 AN: 150694 Hom.: 0 Cov.: 31 AF XY: 0.0000816 AC XY: 6 AN XY: 73512

Gnomad4 AFR AF: 0.000122

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000391

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000976

Gnomad4 NFE AF: 0.0000592

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000480 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2024

This variant, c.126_173del, results in the deletion of 16 amino acid(s) of the SIX3 protein (p.Gly43_Gly58del), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with SIX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1346455). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs747291764; hg19: chr2-45169336;