6-42228526-G-T

Variant names:

• chr6-42228526-G-T
• rs773652505
• NM_001395490.1:c.3458C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001395490.1(TRERF1):​c.3458C>A​(p.Ala1153Glu) 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. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1153V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRERF1 NM_001395490.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.923
• Publications: 2 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.065454334).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001395490.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRERF1	NM_001395490.1	MANE Select	c.3458C>A	p.Ala1153Glu	missense	Exon 18 of 18	NP_001382419.1	A0A8Q3SI57
	TRERF1	NM_001297573.2		c.3482C>A	p.Ala1161Glu	missense	Exon 18 of 18	NP_001284502.1	Q05GC8
	TRERF1	NM_001391983.1		c.3422C>A	p.Ala1141Glu	missense	Exon 18 of 18	NP_001378912.1	Q96PN7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRERF1	ENST00000695948.1	MANE Select	c.3458C>A	p.Ala1153Glu	missense	Exon 18 of 18	ENSP00000512293.1	A0A8Q3SI57
	TRERF1	ENST00000541110.5	TSL:1	c.3482C>A	p.Ala1161Glu	missense	Exon 18 of 18	ENSP00000439689.1	Q05GC8
	TRERF1	ENST00000372922.8	TSL:1	c.3422C>A	p.Ala1141Glu	missense	Exon 18 of 18	ENSP00000362013.4	Q96PN7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	13
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.065	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.92
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.017
Sift	Benign	0.064	T
Sift4G	Benign	0.12	T
Polyphen		0.18	B
Vest4		0.21
MutPred		0.26		Gain of disorder (P = 0.0388)
MVP		0.13
MPC		1.5
ClinPred		0.22	T
GERP RS		3.5
Varity_R		0.047
gMVP		0.31
Mutation Taster		=92/8	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

dbSNP: rs773652505; hg19: chr6-42196264;