14-60713897-T-C

Variant names:

• chr14-60713897-T-C
• rs1895869395
• NM_017420.5:c.1856A>G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017420.5(SIX4):​c.1856A>G​(p.Asn619Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: SIX4 NM_017420.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.837

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049004048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SIX4	NM_017420.5	c.1856A>G	p.Asn619Ser	missense_variant	Exon 3 of 3	ENST00000216513.5	NP_059116.3
SIX4	XM_005267759.3	c.1832A>G	p.Asn611Ser	missense_variant	Exon 4 of 4		XP_005267816.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SIX4	ENST00000216513.5	c.1856A>G	p.Asn619Ser	missense_variant	Exon 3 of 3	1	NM_017420.5	ENSP00000216513.4
SIX4	ENST00000554079.1	n.1273A>G		non_coding_transcript_exon_variant	Exon 4 of 4	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 05, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1856A>G (p.N619S) alteration is located in exon 3 (coding exon 3) of the SIX4 gene. This alteration results from a A to G substitution at nucleotide position 1856, causing the asparagine (N) at amino acid position 619 to be replaced by a serine (S). 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	Benign	0.060
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	6.0
DANN	Benign	0.89
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.56
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.049	T
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	0.90	L
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.21
Sift	Benign	0.15	T
Sift4G	Benign	0.82	T
Polyphen		0.0010	B
Vest4		0.029
MutPred		0.11		Loss of catalytic residue at N619 (P = 0.0179);
MVP		0.40
MPC		0.067
ClinPred		0.086	T
GERP RS		-0.68
Varity_R		0.030
gMVP		0.43

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: rs1895869395; hg19: chr14-61180615;