rs537643024

Variant names:

• chr2-44942165-G-A
• rs537643024
• NM_005413.4:c.61G>A

Your query was ambiguous. Multiple possible variants found:

• chr2-44942165-G-A
• chr2-44942165-G-T

Variant summary

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

The NM_005413.4(SIX3):​c.61G>A​(p.Asp21Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. D21Y) has been classified 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: 3.85
• 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 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005413.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	NM_005413.4	MANE Select	c.61G>A	p.Asp21Asn	missense	Exon 1 of 2	NP_005404.1	O95343

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX3	ENST00000260653.5	TSL:1 MANE Select	c.61G>A	p.Asp21Asn	missense	Exon 1 of 2	ENSP00000260653.3	O95343
	ENSG00000225156	ENST00000760330.1		n.135+7789G>A		intron	N/A
	SIX3-AS1	ENST00000760560.1		n.389-1332C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Holoprosencephaly 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.046
Eigen_PC	Benign	-0.017
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.90	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	0.81	L
PhyloP100		3.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.56	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.023	D
Sift4G	Benign	0.13	T
Polyphen		0.65	P
Vest4		0.28
MutPred		0.37		Gain of sheet (P = 0.0149)
MVP		0.93
MPC		1.0
ClinPred		0.65	D
GERP RS		2.7
PromoterAI		-0.080	Neutral
Varity_R		0.13
gMVP		0.67
Mutation Taster		=75/25	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: rs537643024; hg19: chr2-45169304; COSMIC: COSV53228551; COSMIC: COSV53228551;