chr2-44944703-A-G

Variant names:

• chr2-44944703-A-G
• rs338074
• NM_005413.4:c.942A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005413.4(SIX3):​c.942A>G​(p.Ala314Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.926 in 1,586,652 control chromosomes in the GnomAD database, including 680,806 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (66957 hom., cov: 30)
  • Exomes 𝑓: 0.92 (613849 hom.)
• Consequence: SIX3 NM_005413.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.128
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-44944703-A-G is Benign according to our data. Variant chr2-44944703-A-G is described in ClinVar as Benign. ClinVar VariationId is 167690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.128 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

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.942A>G	p.Ala314Ala	synonymous	Exon 2 of 2	NP_005404.1	O95343

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.942A>G	p.Ala314Ala	synonymous	Exon 2 of 2	ENSP00000260653.3	O95343
	SIX3-AS1	ENST00000760561.1		n.49T>C		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000225156	ENST00000760330.1		n.135+10327A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142500 AN: 151960 Hom.: 66913 Cov.: 30

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.959

Gnomad AMR AF: 0.925

Gnomad ASJ AF: 0.922

Gnomad EAS AF: 0.984

Gnomad SAS AF: 0.881

Gnomad FIN AF: 0.924

Gnomad MID AF: 0.939

Gnomad NFE AF: 0.922

Gnomad OTH AF: 0.933

GnomAD2 exomes AF: 0.925 AC: 197167 AN: 213246 AF XY: 0.921

Gnomad AFR exome AF: 0.973

Gnomad AMR exome AF: 0.931

Gnomad ASJ exome AF: 0.925

Gnomad EAS exome AF: 0.984

Gnomad FIN exome AF: 0.919

Gnomad NFE exome AF: 0.920

Gnomad OTH exome AF: 0.922

GnomAD4 exome AF: 0.925 AC: 1326848 AN: 1434578 Hom.: 613849 Cov.: 68 AF XY: 0.924 AC XY: 658339 AN XY: 712870

African (AFR) AF: 0.973 AC: 32205 AN: 33090

American (AMR) AF: 0.933 AC: 40456 AN: 43368

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 23977 AN: 25884

East Asian (EAS) AF: 0.978 AC: 37951 AN: 38786

South Asian (SAS) AF: 0.886 AC: 74616 AN: 84252

European-Finnish (FIN) AF: 0.920 AC: 34681 AN: 37708

Middle Eastern (MID) AF: 0.919 AC: 5283 AN: 5748

European-Non Finnish (NFE) AF: 0.924 AC: 1022208 AN: 1105994

Other (OTH) AF: 0.928 AC: 55471 AN: 59748

GnomAD4 genome AF: 0.938 AC: 142600 AN: 152074 Hom.: 66957 Cov.: 30 AF XY: 0.936 AC XY: 69587 AN XY: 74320

African (AFR) AF: 0.974 AC: 40422 AN: 41500

American (AMR) AF: 0.925 AC: 14151 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.922 AC: 3199 AN: 3470

East Asian (EAS) AF: 0.984 AC: 5041 AN: 5124

South Asian (SAS) AF: 0.881 AC: 4218 AN: 4788

European-Finnish (FIN) AF: 0.924 AC: 9808 AN: 10616

Middle Eastern (MID) AF: 0.932 AC: 272 AN: 292

European-Non Finnish (NFE) AF: 0.922 AC: 62642 AN: 67954

Other (OTH) AF: 0.932 AC: 1972 AN: 2116

Alfa AF: 0.929 Hom.: 120612

Bravo AF: 0.942

Asia WGS AF: 0.911 AC: 3163 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Holoprosencephaly 2 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.69
PhyloP100		0.13
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs338074; hg19: chr2-45171842; COSMIC: COSV108073996; COSMIC: COSV108073996;