chr1-54737582-G-A

Variant names:

• chr1-54737582-G-A
• rs1427977874
• NM_004623.5:c.979G>A

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.979G>A​(p.Val327Ile) variant causes a missense, splice region 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. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V327L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTC4 NM_004623.5 missense, splice_region
• Scores: Splicing: ADA: 0.2923
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.850
• 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=0.113827586).

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.979G>A	p.Val327Ile	missense splice_region	Exon 9 of 10	NP_004614.3
	TTC4	NM_001291333.2		c.682G>A	p.Val228Ile	missense splice_region	Exon 7 of 8	NP_001278262.1
	MROH7-TTC4	NR_037639.2		n.5157G>A		splice_region non_coding_transcript_exon	Exon 32 of 33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC4	ENST00000371281.4	TSL:1 MANE Select	c.979G>A	p.Val327Ile	missense splice_region	Exon 9 of 10	ENSP00000360329.3	O95801
	MROH7-TTC4	ENST00000414150.6	TSL:2	n.*681G>A		splice_region non_coding_transcript_exon	Exon 32 of 33	ENSP00000410192.2	A0A0A0MT08
	MROH7-TTC4	ENST00000414150.6	TSL:2	n.*681G>A		3_prime_UTR	Exon 32 of 33	ENSP00000410192.2	A0A0A0MT08

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0045	T
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.012
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.85
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.034
Sift	Benign	0.31	T
Sift4G	Benign	0.42	T
Polyphen		0.21	B
Vest4		0.11
MVP		0.40
MPC		0.045
ClinPred		0.30	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.053
gMVP		0.14
Mutation Taster		=78/22	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.29
dbscSNV1_RF	Benign	0.31
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: rs1427977874; hg19: chr1-55203255;