rs751280287

Variant names:

• chr2-44944648-C-G
• rs751280287
• NM_005413.4:c.887C>G

Your query was ambiguous. Multiple possible variants found:

• chr2-44944648-C-G
• chr2-44944648-C-T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_005413.4(SIX3):​c.887C>G​(p.Ser296Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000119 in 1,574,258 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.47
• 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: Likely_benign. The variant received -1 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000127 (181/1422054) while in subpopulation NFE AF = 0.00016 (176/1099924). AF 95% confidence interval is 0.00014. There are 0 homozygotes in GnomAdExome4. There are 91 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.887C>G	p.Ser296Trp	missense	Exon 2 of 2	NP_005404.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.887C>G	p.Ser296Trp	missense	Exon 2 of 2	ENSP00000260653.3
	SIX3-AS1	ENST00000760561.1		n.104G>C		non_coding_transcript_exon	Exon 1 of 2
	ENSG00000225156	ENST00000760330.1		n.135+10272C>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000809 AC: 15 AN: 185338 AF XY: 0.0000971

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000132

Gnomad NFE exome AF: 0.000170

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 181 AN: 1422054 Hom.: 0 Cov.: 31 AF XY: 0.000129 AC XY: 91 AN XY: 705998

African (AFR) AF: 0.00 AC: 0 AN: 32654

American (AMR) AF: 0.00 AC: 0 AN: 42062

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25674

East Asian (EAS) AF: 0.00 AC: 0 AN: 37658

South Asian (SAS) AF: 0.00 AC: 0 AN: 83128

European-Finnish (FIN) AF: 0.0000278 AC: 1 AN: 36020

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5738

European-Non Finnish (NFE) AF: 0.000160 AC: 176 AN: 1099924

Other (OTH) AF: 0.0000676 AC: 4 AN: 59196

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74358

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.000131 AC: 2 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.000112 AC: 13

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly 2 (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	-0.060
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Benign	0.69	N
PhyloP100		4.5
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.60
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.44
MutPred		0.22		Loss of phosphorylation at S296 (P = 0.0093)
MVP		0.98
MPC		2.5
ClinPred		0.46	T
GERP RS		3.5
Varity_R		0.41
gMVP		0.76
Mutation Taster		=41/59	disease causing

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: rs751280287; hg19: chr2-45171787;