2-44942156-A-T

Variant names:

• chr2-44942156-A-T
• rs551637040
• NM_005413.4:c.52A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_005413.4(SIX3):​c.52A>T​(p.Asn18Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SIX3 NM_005413.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.85

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX3	NM_005413.4	c.52A>T	p.Asn18Tyr	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.52A>T	p.Asn18Tyr	missense_variant	Exon 1 of 2	1	NM_005413.4	ENSP00000260653.3
SIX3-AS1	ENST00000419364.3	n.-240T>A		upstream_gene_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Holoprosencephaly 2 Uncertain:1

Oct 23, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with SIX3-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 18 of the SIX3 protein (p.Asn18Tyr). The asparagine residue is moderately conserved and there is a large physicochemical difference between asparagine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.86	N
REVEL	Uncertain	0.47
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		0.97	D
Vest4		0.84
MutPred		0.23		Loss of disorder (P = 0.0393);
MVP		0.91
MPC		2.3
ClinPred		0.69	D
GERP RS		2.7
Varity_R		0.15
gMVP		0.78

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: rs551637040; hg19: chr2-45169295;