rs1363787420

Variant names:

• chr1-54715955-C-T
• rs1363787420
• NM_004623.5:c.47C>T

Variant summary

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

The NM_004623.5(TTC4):​c.47C>T​(p.Ser16Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000481 in 1,454,780 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TTC4 NM_004623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.56
• Publications: 0 publications found

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]

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]

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=0.14845005).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC4	NM_004623.5	MANE Select	c.47C>T	p.Ser16Leu	missense	Exon 1 of 10	NP_004614.3
	TTC4	NM_001291333.2		c.47C>T	p.Ser16Leu	missense	Exon 1 of 8	NP_001278262.1
	MROH7-TTC4	NR_037639.2		n.4289+345C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC4	ENST00000371281.4	TSL:1 MANE Select	c.47C>T	p.Ser16Leu	missense	Exon 1 of 10	ENSP00000360329.3	O95801
	MROH7-TTC4	ENST00000414150.6	TSL:2	n.3818+345C>T		intron	N/A	ENSP00000410192.2	A0A0A0MT08
	TTC4	ENST00000934475.1		c.47C>T	p.Ser16Leu	missense	Exon 1 of 10	ENSP00000604534.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000420 AC: 1 AN: 237814 AF XY: 0.00000778

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000936

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000481 AC: 7 AN: 1454780 Hom.: 0 Cov.: 31 AF XY: 0.00000830 AC XY: 6 AN XY: 723016

African (AFR) AF: 0.00 AC: 0 AN: 33238

American (AMR) AF: 0.00 AC: 0 AN: 44046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39332

South Asian (SAS) AF: 0.00 AC: 0 AN: 84806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52844

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5518

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108920

Other (OTH) AF: 0.00 AC: 0 AN: 60112

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.051	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.6
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.024
Sift	Benign	0.031	D
Sift4G	Uncertain	0.045	D
Polyphen		0.23	B
Vest4		0.18
MutPred		0.30		Loss of phosphorylation at S16 (P = 0.0367)
MVP		0.37
MPC		0.052
ClinPred		0.85	D
GERP RS		4.0
PromoterAI		-0.046	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.17
gMVP		0.24
Mutation Taster		=82/18	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: rs1363787420; hg19: chr1-55181628;