chr2-44942231-G-A

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005413.4(SIX3):​c.127G>A​(p.Gly43Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,432,182 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G43C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.440
• 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]

ENSG00000225156 (HGNC:):

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2163772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4	c.127G>A	p.Gly43Ser	missense_variant	Exon 1 of 2	ENST00000260653.5	NP_005404.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX3	ENST00000260653.5	c.127G>A	p.Gly43Ser	missense_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432182 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 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: 0.00000181 AC: 2 AN: 1103744

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

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.040	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.44
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	0.030	N
REVEL	Benign	0.17
Sift	Benign	0.094	T
Sift4G	Benign	0.073	T
Polyphen		0.0010	B
Vest4		0.29
MutPred		0.23		Gain of phosphorylation at G43 (P = 0.0037);
MVP		0.80
MPC		1.0
ClinPred		0.18	T
GERP RS		1.8
Varity_R		0.049
gMVP		0.56
Mutation Taster		=88/12	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;