1-54731583-A-T

Variant names:

• chr1-54731583-A-T
• rs768676007
• NM_004623.5:c.779A>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004623.5(TTC4):​c.779A>T​(p.Asn260Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,840 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TTC4 NM_004623.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.26

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC4	NM_004623.5	c.779A>T	p.Asn260Ile	missense_variant	Exon 7 of 10	ENST00000371281.4	NP_004614.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC4	ENST00000371281.4	c.779A>T	p.Asn260Ile	missense_variant	Exon 7 of 10	1	NM_004623.5	ENSP00000360329.3
MROH7-TTC4	ENST00000414150.6	n.*481A>T		non_coding_transcript_exon_variant	Exon 30 of 33	2		ENSP00000410192.2
MROH7-TTC4	ENST00000414150.6	n.*481A>T		3_prime_UTR_variant	Exon 30 of 33	2		ENSP00000410192.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000199 AC: 5 AN: 251188 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135752

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461840 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.779A>T (p.N260I) alteration is located in exon 7 (coding exon 7) of the TTC4 gene. This alteration results from a A to T substitution at nucleotide position 779, causing the asparagine (N) at amino acid position 260 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0088	T
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.095	T
Polyphen		0.91	P
Vest4		0.61
MVP		0.67
MPC		0.075
ClinPred		0.47	T
GERP RS		4.9
Varity_R		0.15
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs768676007; hg19: chr1-55197256;