rs199823175

Variant names:

• chr2-44942213-G-C
• rs199823175
• NM_005413.4:c.109G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-44942213-G-C
• chr2-44942213-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005413.4(SIX3):​c.109G>C​(p.Gly37Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000278 in 1,438,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. G37C) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.103

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19368196).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4	c.109G>C	p.Gly37Arg	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.109G>C	p.Gly37Arg	missense_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000278 AC: 4 AN: 1438724 Hom.: 0 Cov.: 32 AF XY: 0.00000140 AC XY: 1 AN XY: 715778

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: 0.00000361

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 21, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SIX3 c.109G>C (p.Gly37Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 231504 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.109G>C in individuals affected with SIX3-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.34
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.50	T
M_CAP	Pathogenic	0.72	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.59	N
REVEL	Benign	0.17
Sift	Benign	0.24	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.067	B
Vest4		0.20
MutPred		0.34		Gain of methylation at G37 (P = 0.0351);
MVP		0.53
MPC		1.2
ClinPred		0.12	T
GERP RS		-0.74
Varity_R		0.098
gMVP		0.46

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: rs199823175; hg19: chr2-45169352;