rs1436891421

chr2-44942231-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

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 (★★).

• 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:2
• Conservation: PhyloP100: 0.440

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.39806223).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SIX3	NM_005413.4	c.127G>T	p.Gly43Cys	missense_variant	1/2	ENST00000260653.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SIX3	ENST00000260653.5	c.127G>T	p.Gly43Cys	missense_variant	1/2	1	NM_005413.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000272

Gnomad4 OTH exome AF: 0.00

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

Gnomad4 AFR AF: 0.0000243

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000741

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 22, 2016

- -

Schizencephaly;C1834877:Holoprosencephaly 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	0.99	N
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1436891421; hg19: chr2-45169370;