rs1180937

Variant names:

• chr1-54725971-T-C
• rs1180937
• NM_004623.5:c.595-2375T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004623.5(TTC4):​c.595-2375T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.804 in 152,056 control chromosomes in the GnomAD database, including 49,623 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.80 (49623 hom., cov: 31)
• Consequence: TTC4 NM_004623.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.746
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.89 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC4	NM_004623.5	c.595-2375T>C		intron_variant	Intron 5 of 9	ENST00000371281.4	NP_004614.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC4	ENST00000371281.4	c.595-2375T>C		intron_variant	Intron 5 of 9	1	NM_004623.5	ENSP00000360329.3
MROH7-TTC4	ENST00000414150.6	n.*297-2375T>C		intron_variant	Intron 28 of 32	2		ENSP00000410192.2

Frequencies

GnomAD3 genomes AF: 0.804 AC: 122221 AN: 151938 Hom.: 49605 Cov.: 31

Gnomad AFR AF: 0.684

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.816

Gnomad ASJ AF: 0.853

Gnomad EAS AF: 0.911

Gnomad SAS AF: 0.877

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.841

Gnomad OTH AF: 0.815

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.804 AC: 122285 AN: 152056 Hom.: 49623 Cov.: 31 AF XY: 0.811 AC XY: 60268 AN XY: 74342

African (AFR) AF: 0.684 AC: 28335 AN: 41430

American (AMR) AF: 0.816 AC: 12465 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.853 AC: 2957 AN: 3468

East Asian (EAS) AF: 0.912 AC: 4713 AN: 5168

South Asian (SAS) AF: 0.876 AC: 4219 AN: 4816

European-Finnish (FIN) AF: 0.911 AC: 9635 AN: 10578

Middle Eastern (MID) AF: 0.748 AC: 220 AN: 294

European-Non Finnish (NFE) AF: 0.841 AC: 57190 AN: 68000

Other (OTH) AF: 0.817 AC: 1726 AN: 2112

Alfa AF: 0.835 Hom.: 100887

Bravo AF: 0.792

Asia WGS AF: 0.891 AC: 3097 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.21
DANN	Benign	0.92
PhyloP100		-0.75
Mutation Taster		=100/0	polymorphism (auto)

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: rs1180937; hg19: chr1-55191644; COSMIC: COSV64884487;