rs7178

Variant names:

• chr11-69654262-A-G
• rs7178
• ENST00000538554.6:c.547T>C

Variant summary

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

The ENST00000538554.6(LTO1):​c.547T>C​(p.Tyr183His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 702,534 control chromosomes in the GnomAD database, including 1,782 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/14 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 0.055 (321 hom., cov: 32)
  • Exomes 𝑓: 0.065 (1461 hom.)
• Consequence: LTO1 ENST00000538554.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.00
• Publications: 23 publications found

Genes affected

LTO1 (HGNC:17589): (LTO1 maturation factor of ABCE1) Involved in protein maturation by [4Fe-4S] cluster transfer; ribosomal large subunit biogenesis; and translational initiation. Predicted to be located in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

CCND1 (HGNC:1582): (cyclin D1) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protein abundance throughout the cell cycle. Cyclins function as regulators of CDK kinases. Different cyclins exhibit distinct expression and degradation patterns which contribute to the temporal coordination of each mitotic event. This cyclin forms a complex with and functions as a regulatory subunit of CDK4 or CDK6, whose activity is required for cell cycle G1/S transition. This protein has been shown to interact with tumor suppressor protein Rb and the expression of this gene is regulated positively by Rb. Mutations, amplification and overexpression of this gene, which alters cell cycle progression, are observed frequently in a variety of human cancers. [provided by RefSeq, Dec 2019]

CCND1 Gene-Disease associations (from GenCC):

• von Hippel-Lindau disease

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015180409).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0777 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCND1	NM_053056.3	c.*2980A>G		3_prime_UTR_variant	Exon 5 of 5	ENST00000227507.3	NP_444284.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LTO1	ENST00000538554.6	c.547T>C	p.Tyr183His	missense_variant	Exon 6 of 7	2		ENSP00000446428.3
CCND1	ENST00000227507.3	c.*2980A>G		3_prime_UTR_variant	Exon 5 of 5	1	NM_053056.3	ENSP00000227507.2
LTO1	ENST00000542515.5	n.1954T>C		non_coding_transcript_exon_variant	Exon 2 of 3	2
LTO1	ENST00000569105.5	n.445T>C		non_coding_transcript_exon_variant	Exon 5 of 6	2

Frequencies

GnomAD3 genomes AF: 0.0551 AC: 8380 AN: 152126 Hom.: 321 Cov.: 32

Gnomad AFR AF: 0.0123

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.0352

Gnomad ASJ AF: 0.0781

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0155

Gnomad FIN AF: 0.130

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0632

GnomAD2 exomes AF: 0.0516 AC: 6752 AN: 130854 AF XY: 0.0509

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0351

Gnomad ASJ exome AF: 0.0806

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.124

Gnomad NFE exome AF: 0.0765

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0651 AC: 35828 AN: 550290 Hom.: 1461 Cov.: 0 AF XY: 0.0631 AC XY: 18788 AN XY: 297880

African (AFR) AF: 0.0134 AC: 212 AN: 15808

American (AMR) AF: 0.0355 AC: 1232 AN: 34716

Ashkenazi Jewish (ASJ) AF: 0.0752 AC: 1506 AN: 20030

East Asian (EAS) AF: 0.00 AC: 0 AN: 32104

South Asian (SAS) AF: 0.0223 AC: 1403 AN: 62776

European-Finnish (FIN) AF: 0.122 AC: 4046 AN: 33200

Middle Eastern (MID) AF: 0.0510 AC: 208 AN: 4076

European-Non Finnish (NFE) AF: 0.0798 AC: 25299 AN: 316976

Other (OTH) AF: 0.0628 AC: 1922 AN: 30604

GnomAD4 genome AF: 0.0550 AC: 8379 AN: 152244 Hom.: 321 Cov.: 32 AF XY: 0.0561 AC XY: 4177 AN XY: 74426

African (AFR) AF: 0.0122 AC: 508 AN: 41572

American (AMR) AF: 0.0352 AC: 538 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0781 AC: 271 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4830

European-Finnish (FIN) AF: 0.130 AC: 1379 AN: 10606

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0794 AC: 5402 AN: 68004

Other (OTH) AF: 0.0625 AC: 132 AN: 2112

Alfa AF: 0.0718 Hom.: 974

Bravo AF: 0.0469

TwinsUK AF: 0.0793 AC: 294

ALSPAC AF: 0.0732 AC: 282

ExAC AF: 0.0302 AC: 554

Asia WGS AF: 0.0100 AC: 36 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	16
DANN	Benign	0.76
DEOGEN2	Benign	0.0033	T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
PhyloP100		2.0
REVEL	Benign	0.024
Sift4G	Benign	0.49	T
Vest4		0.12
ClinPred		0.024	T
GERP RS		2.1
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: rs7178; hg19: chr11-69469030; COSMIC: COSV57121029; COSMIC: COSV57121029;