rs1436891421

Variant names:

• chr2-44942231-G-T
• rs1436891421
• NM_005413.4:c.127G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-44942231-G-T
• chr2-44942231-G-A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_005413.4(SIX3):​c.127G>T​(p.Gly43Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000227 in 1,582,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.440
• Publications: 1 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]

ENSG00000225156 (HGNC:):

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39806223).

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.127G>T	p.Gly43Cys	missense	Exon 1 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.127G>T	p.Gly43Cys	missense	Exon 1 of 2	ENSP00000260653.3	O95343
	ENSG00000225156	ENST00000760330.1		n.135+7855G>T		intron	N/A
	SIX3-AS1	ENST00000760560.1		n.389-1398C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000399 AC: 6 AN: 150562 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000741

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000209 AC: 30 AN: 1432182 Hom.: 0 Cov.: 32 AF XY: 0.0000211 AC XY: 15 AN XY: 712486

African (AFR) AF: 0.00 AC: 0 AN: 32726

American (AMR) AF: 0.00 AC: 0 AN: 43950

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25630

East Asian (EAS) AF: 0.00 AC: 0 AN: 38968

South Asian (SAS) AF: 0.00 AC: 0 AN: 84608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38058

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5138

European-Non Finnish (NFE) AF: 0.0000272 AC: 30 AN: 1103744

Other (OTH) AF: 0.00 AC: 0 AN: 59360

GnomAD4 genome AF: 0.0000399 AC: 6 AN: 150562 Hom.: 0 Cov.: 31 AF XY: 0.0000272 AC XY: 2 AN XY: 73450

African (AFR) AF: 0.0000243 AC: 1 AN: 41164

American (AMR) AF: 0.00 AC: 0 AN: 15120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5134

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10138

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

European-Non Finnish (NFE) AF: 0.0000741 AC: 5 AN: 67472

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly 2 (1)
-	1	-	not provided (1)
-	1	-	Schizencephaly;C1834877:Holoprosencephaly 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.033
Eigen_PC	Benign	-0.015
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.44
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.75	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.85	P
Vest4		0.38
MutPred		0.43		Loss of loop (P = 0.4412)
MVP		0.92
MPC		1.1
ClinPred		0.37	T
GERP RS		1.8
Varity_R		0.20
gMVP		0.76
Mutation Taster		=86/14	polymorphism

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: rs1436891421; hg19: chr2-45169370;