chr1-150816812-G-T

Position:

• chr1-150816812-G-T

Variant summary

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

The NM_001668.4(ARNT):​c.1778C>A​(p.Thr593Asn) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ARNT NM_001668.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.448

Genes affected

ARNT (HGNC:700): (aryl hydrocarbon receptor nuclear translocator) This gene encodes a protein containing a basic helix-loop-helix domain and two characteristic PAS domains along with a PAC domain. The encoded protein binds to ligand-bound aryl hydrocarbon receptor and aids in the movement of this complex to the nucleus, where it promotes the expression of genes involved in xenobiotic metabolism. This protein is also a co-factor for transcriptional regulation by hypoxia-inducible factor 1. Chromosomal translocation of this locus with the ETV6 (ets variant 6) gene on chromosome 12 have been described in leukemias. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2013]

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=0.055312425).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARNT	NM_001668.4	c.1778C>A	p.Thr593Asn	missense_variant	18/22	ENST00000358595.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARNT	ENST00000358595.10	c.1778C>A	p.Thr593Asn	missense_variant	18/22	1	NM_001668.4	P3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 26, 2022

The c.1778C>A (p.T593N) alteration is located in exon 18 (coding exon 18) of the ARNT gene. This alteration results from a C to A substitution at nucleotide position 1778, causing the threonine (T) at amino acid position 593 to be replaced by an asparagine (N). 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	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	17
DANN	Benign	0.82
DEOGEN2	Benign	0.078	T;.;.;.
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.0027	T
MetaRNN	Benign	0.055	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N;N;.;.
MutationTaster	Benign	0.98	N;N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.15	N;N;N;N
REVEL	Benign	0.16
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	0.18	T;T;T;T
Polyphen		0.0	B;.;B;B
Vest4		0.082
MutPred		0.17		Loss of glycosylation at T593 (P = 0.0022);Loss of glycosylation at T593 (P = 0.0022);.;.;
MVP		0.33
MPC		0.34
ClinPred		0.030	T
GERP RS		0.88
Varity_R		0.024
gMVP		0.24

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: rs1655982592; hg19: chr1-150789288;