4-84497750-A-G

Variant names:

• chr4-84497750-A-G
• NM_006168.3:c.479T>C

Variant summary

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

The NM_006168.3(NKX6-1):​c.479T>C​(p.Leu160Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NKX6-1 NM_006168.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.29
• Publications: 0 publications found

Genes affected

NKX6-1 (HGNC:7839): (NK6 homeobox 1) In the pancreas, NKX6.1 is required for the development of beta cells and is a potent bifunctional transcription regulator that binds to AT-rich sequences within the promoter region of target genes Iype et al. (2004) [PubMed 15056733].[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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
NKX6-1	NM_006168.3	c.479T>C	p.Leu160Pro	missense_variant	Exon 1 of 3	ENST00000295886.5	NP_006159.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX6-1	ENST00000295886.5	c.479T>C	p.Leu160Pro	missense_variant	Exon 1 of 3	1	NM_006168.3	ENSP00000295886.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1127748 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 541042

African (AFR) AF: 0.00 AC: 0 AN: 23212

American (AMR) AF: 0.00 AC: 0 AN: 9316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15222

East Asian (EAS) AF: 0.00 AC: 0 AN: 26924

South Asian (SAS) AF: 0.00 AC: 0 AN: 30650

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3074

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 947326

Other (OTH) AF: 0.00 AC: 0 AN: 45344

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 07, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.479T>C (p.L160P) alteration is located in exon 1 (coding exon 1) of the NKX6-1 gene. This alteration results from a T to C substitution at nucleotide position 479, causing the leucine (L) at amino acid position 160 to be replaced by a proline (P). 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	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.10
Eigen_PC	Benign	0.019
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Uncertain	0.098	D
MutationAssessor	Benign	1.5	L
PhyloP100		3.3
PrimateAI	Pathogenic	0.96	D
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.036	D
Polyphen		0.048	B
Vest4		0.43
MutPred		0.35		Loss of helix (P = 0.0123);
MVP		1.0
MPC		1.2
ClinPred		0.83	D
GERP RS		4.0
Varity_R		0.48
gMVP		0.84
Mutation Taster		=48/52	disease causing

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

hg19: chr4-85418903;