6-42228466-A-T

Variant names:

• chr6-42228466-A-T
• NM_001395490.1:c.3518T>A

Variant summary

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

The NM_001395490.1(TRERF1):​c.3518T>A​(p.Ile1173Asn) 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. 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: TRERF1 NM_001395490.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08
• Publications: 0 publications found

Genes affected

TRERF1 (HGNC:18273): (transcriptional regulating factor 1) This gene encodes a zinc-finger transcriptional regulating protein which interacts with CBP/p300 to regulate the human gene CYP11A1. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2014]

TRERF1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

LOC105375061 (HGNC:):

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=0.11528534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRERF1	NM_001395490.1	c.3518T>A	p.Ile1173Asn	missense_variant	Exon 18 of 18	ENST00000695948.1	NP_001382419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRERF1	ENST00000695948.1	c.3518T>A	p.Ile1173Asn	missense_variant	Exon 18 of 18		NM_001395490.1	ENSP00000512293.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3482T>A (p.I1161N) alteration is located in exon 18 (coding exon 14) of the TRERF1 gene. This alteration results from a T to A substitution at nucleotide position 3482, causing the isoleucine (I) at amino acid position 1161 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	0.13
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.024	T;T;.;.;.
Eigen	Benign	-0.076
Eigen_PC	Benign	0.078
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.12	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	.;N;.;.;.
PhyloP100		3.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;N;.;N;N
REVEL	Benign	0.044
Sift	Uncertain	0.0060	D;D;.;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		0.090	B;B;B;.;B
Vest4		0.36
MutPred		0.40		Gain of disorder (P = 0.0301);.;.;.;.;
MVP		0.20
MPC		1.4
ClinPred		0.45	T
GERP RS		4.6
Varity_R		0.23
gMVP		0.19
Mutation Taster		=97/3	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

hg19: chr6-42196204;