6-42232757-T-G

Variant names:

• chr6-42232757-T-G
• NM_001395490.1:c.3238A>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001395490.1(TRERF1):​c.3238A>C​(p.Lys1080Gln) 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. 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: 5.83
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31404024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRERF1	NM_001395490.1	c.3238A>C	p.Lys1080Gln	missense_variant	Exon 17 of 18	ENST00000695948.1	NP_001382419.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRERF1	ENST00000695948.1	c.3238A>C	p.Lys1080Gln	missense_variant	Exon 17 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

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3202A>C (p.K1068Q) alteration is located in exon 17 (coding exon 13) of the TRERF1 gene. This alteration results from a A to C substitution at nucleotide position 3202, causing the lysine (K) at amino acid position 1068 to be replaced by a glutamine (Q). 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	Pathogenic	0.63
BayesDel_addAF	Benign	-0.038	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.31	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	.;L;.;.;.
PhyloP100		5.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.8	N;N;D;N;N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;T;D;D
Polyphen		1.0	D;D;D;.;D
Vest4		0.54
MutPred		0.29		Loss of ubiquitination at K1088 (P = 0.0022);.;.;.;.;
MVP		0.58
MPC		0.69
ClinPred		0.87	D
GERP RS		5.4
Varity_R		0.24
gMVP		0.38
Mutation Taster		=78/22	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: chr6-42200495;