2-44941782-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_005413.4(SIX3):c.-323C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 332,676 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0049 (4 hom., cov: 30)
  • Exomes 𝑓: 0.0054 (7 hom.)
• Consequence: SIX3 NM_005413.4 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.44

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]

SIX3-AS1 (HGNC:40532): (SIX3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-44941782-C-T is Benign according to our data. Variant chr2-44941782-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1197315.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00488 (742/152084) while in subpopulation AMR AF= 0.00798 (122/15288). AF 95% confidence interval is 0.00683. There are 4 homozygotes in gnomad4. There are 346 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 742 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX3	NM_005413.4	c.-323C>T		5_prime_UTR_variant	1/2	ENST00000260653.5
SIX3-AS1	NR_103786.1	n.97G>A		non_coding_transcript_exon_variant	1/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX3	ENST00000260653.5	c.-323C>T		5_prime_UTR_variant	1/2	1	NM_005413.4	P1
SIX3-AS1	ENST00000419364.3	n.135G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00488 AC: 742 AN: 151966 Hom.: 4 Cov.: 30

Gnomad AFR AF: 0.000750

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00799

Gnomad ASJ AF: 0.00864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00444

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.00727

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.00544 AC: 983 AN: 180592 Hom.: 7 Cov.: 0 AF XY: 0.00503 AC XY: 478 AN XY: 95106

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00670

Gnomad4 ASJ exome AF: 0.00723

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000123

Gnomad4 FIN exome AF: 0.00556

Gnomad4 NFE exome AF: 0.00718

Gnomad4 OTH exome AF: 0.00615

GnomAD4 genome AF: 0.00488 AC: 742 AN: 152084 Hom.: 4 Cov.: 30 AF XY: 0.00465 AC XY: 346 AN XY: 74348

Gnomad4 AFR AF: 0.000748

Gnomad4 AMR AF: 0.00798

Gnomad4 ASJ AF: 0.00864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00444

Gnomad4 NFE AF: 0.00727

Gnomad4 OTH AF: 0.00804

Alfa AF: 0.00459 Hom.: 1

Bravo AF: 0.00481

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 16, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	19
Dann	Benign	0.97

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113140425; hg19: chr2-45168921;