2-44941782-C-T

Variant names:

• chr2-44941782-C-T
• rs113140425
• NM_005413.4:c.-323C>T

Variant summary

Our verdict is Benign. The variant received -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 premature start codon gain 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_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.44
• Publications: 0 publications found

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)

ENSG00000225156 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.-323C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	NP_005404.1	O95343
	SIX3	NM_005413.4	MANE Select	c.-323C>T		5_prime_UTR	Exon 1 of 2	NP_005404.1	O95343
	SIX3-AS1	NR_103786.1		n.97G>A		non_coding_transcript_exon	Exon 1 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.-323C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 2	ENSP00000260653.3	O95343
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.-323C>T		5_prime_UTR	Exon 1 of 2	ENSP00000260653.3	O95343
	SIX3-AS1	ENST00000419364.4	TSL:2	n.287G>A		non_coding_transcript_exon	Exon 1 of 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

African (AFR) AF: 0.00102 AC: 6 AN: 5862

American (AMR) AF: 0.00670 AC: 63 AN: 9402

Ashkenazi Jewish (ASJ) AF: 0.00723 AC: 36 AN: 4978

East Asian (EAS) AF: 0.00 AC: 0 AN: 10012

South Asian (SAS) AF: 0.000123 AC: 3 AN: 24454

European-Finnish (FIN) AF: 0.00556 AC: 54 AN: 9716

Middle Eastern (MID) AF: 0.00282 AC: 2 AN: 710

European-Non Finnish (NFE) AF: 0.00718 AC: 757 AN: 105374

Other (OTH) AF: 0.00615 AC: 62 AN: 10084

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

African (AFR) AF: 0.000748 AC: 31 AN: 41464

American (AMR) AF: 0.00798 AC: 122 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00864 AC: 30 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00444 AC: 47 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00727 AC: 494 AN: 67982

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00459 Hom.: 1

Bravo AF: 0.00481

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.97
PhyloP100		1.4
PromoterAI		-0.093	Neutral
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs113140425; hg19: chr2-45168921;