NM_017420.5:c.1852C>A

Variant names:

• chr14-60713901-G-T
• NM_017420.5:c.1852C>A

Variant summary

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

The NM_017420.5(SIX4):​c.1852C>A​(p.His618Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SIX4 NM_017420.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.89
• Publications: 0 publications found

Genes affected

SIX4 (HGNC:10890): (SIX homeobox 4) This gene encodes a member of the homeobox family, subfamily SIX. The drosophila homolog is a nuclear homeoprotein required for eye development. Studies in mouse show that this gene product functions as a transcription factor, and may have a role in the differentiation or maturation of neuronal cells. [provided by RefSeq, May 2010]

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=0.19583341).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017420.5. 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
	SIX4	NM_017420.5	MANE Select	c.1852C>A	p.His618Asn	missense	Exon 3 of 3	NP_059116.3	Q9UIU6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SIX4	ENST00000216513.5	TSL:1 MANE Select	c.1852C>A	p.His618Asn	missense	Exon 3 of 3	ENSP00000216513.4	Q9UIU6
	SIX4	ENST00000554079.1	TSL:1	n.1269C>A		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Uncertain	0.032	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.091	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	0.55	N
PhyloP100		6.9
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.98	N
REVEL	Benign	0.25
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.34	T
Polyphen		0.45	P
Vest4		0.20
MutPred		0.085		Gain of sheet (P = 0.0827)
MVP		0.73
MPC		0.10
ClinPred		0.54	D
GERP RS		5.7
Varity_R		0.14
gMVP		0.36
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

hg19: chr14-61180619;