Genetic Variant NM_004623.5:c.786T>G (chr1-54731590-T-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004623.5(TTC4):c.786T>G(p.His262Gln) 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. 16/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H262R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Consequence

TTC4
NM_004623.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.13

Publications

0 publications found

Variant links:

Genes affected

TTC4 (HGNC:12394): (tetratricopeptide repeat domain 4) This gene encodes a protein that contains tetratricopeptide (TPR) repeats, which often mediate protein-protein interactions and chaperone activity. The encoded protein interacts with heat shock proteins 70 and 90. Alternative splicing results in multiple transcript variants. Naturally-occuring readthrough transcription occurs from upstream gene MROH (maestro heat-like repeat family member 7) to this gene. [provided by RefSeq, Apr 2014]

TTC4 links:

MROH7-TTC4 (HGNC:49180): (MROH7-TTC4 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring MROH7 (maestro heat-like repeat family member 7) and TTC4 (tetratricopeptide repeat domain 4) genes. Alternative splicing results in multiple transcript variants, which are candidates for nonsense-mediated mRNA decay (NMD) and are unlikely to produce protein products. [provided by RefSeq, Aug 2013]

MROH7-TTC4 links:

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ACMG classification

Classification was made for transcript

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=0.022090048).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004623.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TTC4	NM_004623.5	MANE Select	c.786T>G	p.His262Gln	missense	Exon 7 of 10	NP_004614.3
TTC4	NM_001291333.2		c.681+3158T>G		intron	N/A	NP_001278262.1
MROH7-TTC4	NR_037639.2		n.4964T>G		non_coding_transcript_exon	Exon 30 of 33

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TTC4	ENST00000371281.4	TSL:1 MANE Select	c.786T>G	p.His262Gln	missense	Exon 7 of 10	ENSP00000360329.3	O95801
MROH7-TTC4	ENST00000414150.6	TSL:2	n.*488T>G		non_coding_transcript_exon	Exon 30 of 33	ENSP00000410192.2	A0A0A0MT08
MROH7-TTC4	ENST00000414150.6	TSL:2	n.*488T>G		3_prime_UTR	Exon 30 of 33	ENSP00000410192.2	A0A0A0MT08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.58

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0020

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.031

LIST_S2

Benign

0.57

M_CAP

Benign

0.0031

MetaRNN

Benign

0.022

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.11

PhyloP100

-4.1

PrimateAI

Benign

0.24

PROVEAN

Benign

0.43

REVEL

Benign

0.019

Sift

Benign

0.31

Sift4G

Benign

0.29

Polyphen

0.0010

Vest4

0.14

MVP

0.14

MPC

0.064

ClinPred

0.040

GERP RS

-5.3

Varity_R

0.033

gMVP

0.18

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over