chr1-54716627-T-A

Variant names:

• chr1-54716627-T-A
• rs1147990
• NM_004623.5:c.139T>A

Variant summary

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

The ENST00000371281.4(TTC4):​c.139T>A​(p.Ser47Thr) variant causes a missense change. The variant allele was found at a frequency of 0.545 in 1,611,986 control chromosomes in the GnomAD database, including 247,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.55 (23931 hom., cov: 32)
  • Exomes 𝑓: 0.54 (223452 hom.)
• Consequence: TTC4 ENST00000371281.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.51
• Publications: 32 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 (MetaRNN=9.798943E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.944 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000371281.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC4	NM_004623.5	MANE Select	c.139T>A	p.Ser47Thr	missense	Exon 2 of 10	NP_004614.3
	TTC4	NM_001291333.2		c.139T>A	p.Ser47Thr	missense	Exon 2 of 8	NP_001278262.1
	MROH7-TTC4	NR_037639.2		n.4317T>A		non_coding_transcript_exon	Exon 25 of 33

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC4	ENST00000371281.4	TSL:1 MANE Select	c.139T>A	p.Ser47Thr	missense	Exon 2 of 10	ENSP00000360329.3
	MROH7-TTC4	ENST00000414150.6	TSL:2	n.3846T>A		non_coding_transcript_exon	Exon 25 of 33	ENSP00000410192.2
	TTC4	ENST00000371284.9	TSL:5	n.305T>A		non_coding_transcript_exon	Exon 2 of 10

Frequencies

GnomAD3 genomes AF: 0.552 AC: 83895 AN: 151904 Hom.: 23914 Cov.: 32

Gnomad AFR AF: 0.538

Gnomad AMI AF: 0.674

Gnomad AMR AF: 0.568

Gnomad ASJ AF: 0.555

Gnomad EAS AF: 0.966

Gnomad SAS AF: 0.733

Gnomad FIN AF: 0.535

Gnomad MID AF: 0.509

Gnomad NFE AF: 0.515

Gnomad OTH AF: 0.536

GnomAD2 exomes AF: 0.596 AC: 149236 AN: 250576 AF XY: 0.597

Gnomad AFR exome AF: 0.540

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.560

Gnomad EAS exome AF: 0.962

Gnomad FIN exome AF: 0.527

Gnomad NFE exome AF: 0.521

Gnomad OTH exome AF: 0.557

GnomAD4 exome AF: 0.545 AC: 795131 AN: 1459964 Hom.: 223452 Cov.: 39 AF XY: 0.550 AC XY: 399290 AN XY: 726326

African (AFR) AF: 0.543 AC: 18141 AN: 33418

American (AMR) AF: 0.614 AC: 27344 AN: 44566

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 14721 AN: 26090

East Asian (EAS) AF: 0.979 AC: 38867 AN: 39686

South Asian (SAS) AF: 0.718 AC: 61807 AN: 86106

European-Finnish (FIN) AF: 0.527 AC: 27968 AN: 53088

Middle Eastern (MID) AF: 0.566 AC: 3258 AN: 5760

European-Non Finnish (NFE) AF: 0.512 AC: 569335 AN: 1110918

Other (OTH) AF: 0.558 AC: 33690 AN: 60332

GnomAD4 genome AF: 0.552 AC: 83957 AN: 152022 Hom.: 23931 Cov.: 32 AF XY: 0.557 AC XY: 41372 AN XY: 74312

African (AFR) AF: 0.538 AC: 22316 AN: 41444

American (AMR) AF: 0.568 AC: 8686 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.555 AC: 1925 AN: 3468

East Asian (EAS) AF: 0.966 AC: 4998 AN: 5172

South Asian (SAS) AF: 0.731 AC: 3528 AN: 4826

European-Finnish (FIN) AF: 0.535 AC: 5647 AN: 10560

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.515 AC: 34961 AN: 67948

Other (OTH) AF: 0.537 AC: 1135 AN: 2112

Alfa AF: 0.536 Hom.: 16872

Bravo AF: 0.556

TwinsUK AF: 0.513 AC: 1903

ALSPAC AF: 0.531 AC: 2045

ESP6500AA AF: 0.552 AC: 2432

ESP6500EA AF: 0.511 AC: 4395

ExAC AF: 0.599 AC: 72680

Asia WGS AF: 0.802 AC: 2788 AN: 3478

EpiCase AF: 0.518

EpiControl AF: 0.520

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.068	T
MetaRNN	Benign	9.8e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.55	N
PhyloP100		6.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.40	N
REVEL	Benign	0.11
Sift	Benign	0.52	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.024
MPC		0.047
ClinPred		0.095	T
GERP RS		4.9
Varity_R		0.039
gMVP		0.35
Mutation Taster		=87/13	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: rs1147990; hg19: chr1-55182300; COSMIC: COSV64884669;