chr2-44942161-C-G

Variant names:

• chr2-44942161-C-G
• rs1666588321
• NM_005413.4:c.57C>G

Variant summary

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

The NM_005413.4(SIX3):​c.57C>G​(p.Phe19Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000691 in 1,446,434 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.62

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)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4	c.57C>G	p.Phe19Leu	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.57C>G	p.Phe19Leu	missense_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3
SIX3-AS1	ENST00000419364.3	n.-245G>C		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446434 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 719958

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Mar 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.57C>G (p.F19L) alteration is located in exon 1 (coding exon 1) of the SIX3 gene. This alteration results from a C to G substitution at nucleotide position 57, causing the phenylalanine (F) at amino acid position 19 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.26	D
MutationAssessor	Benign	0.34	N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-0.55	N
REVEL	Uncertain	0.41
Sift	Benign	0.19	T
Sift4G	Benign	0.32	T
Polyphen		0.97	D
Vest4		0.54
MutPred		0.21		Gain of helix (P = 0.0854);
MVP		0.95
MPC		1.8
ClinPred		0.79	D
GERP RS		2.7
Varity_R		0.23
gMVP		0.74

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: rs1666588321; hg19: chr2-45169300;