4-108165124-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016269.5(LEF1):c.253G>A(p.Asp85Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00836 in 1,614,054 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0062 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0086 (63 hom.)
• Consequence: LEF1 NM_016269.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.40

Genes affected

LEF1 (HGNC:6551): (lymphoid enhancer binding factor 1) This gene encodes a transcription factor belonging to a family of proteins that share homology with the high mobility group protein-1. The protein encoded by this gene can bind to a functionally important site in the T-cell receptor-alpha enhancer, thereby conferring maximal enhancer activity. This transcription factor is involved in the Wnt signaling pathway, and it may function in hair cell differentiation and follicle morphogenesis. Mutations in this gene have been found in somatic sebaceous tumors. This gene has also been linked to other cancers, including androgen-independent prostate cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010001779).
• BP6: Variant 4-108165124-C-T is Benign according to our data. Variant chr4-108165124-C-T is described in ClinVar as [Benign]. Clinvar id is 773869.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00858 (12540/1461818) while in subpopulation SAS AF= 0.0167 (1441/86246). AF 95% confidence interval is 0.016. There are 63 homozygotes in gnomad4_exome. There are 6355 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 951 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LEF1	NM_016269.5	c.253G>A	p.Asp85Asn	missense_variant	2/12	ENST00000265165.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LEF1	ENST00000265165.6	c.253G>A	p.Asp85Asn	missense_variant	2/12	1	NM_016269.5

Frequencies

GnomAD3 genomes AF: 0.00625 AC: 951 AN: 152118 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00877

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00869

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00792

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00818 AC: 2058 AN: 251482 Hom.: 11 AF XY: 0.00870 AC XY: 1183 AN XY: 135910

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00971

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.00228

Gnomad SAS exome AF: 0.0163

Gnomad FIN exome AF: 0.00952

Gnomad NFE exome AF: 0.00766

Gnomad OTH exome AF: 0.00896

GnomAD4 exome AF: 0.00858 AC: 12540 AN: 1461818 Hom.: 63 Cov.: 30 AF XY: 0.00874 AC XY: 6355 AN XY: 727204

Gnomad4 AFR exome AF: 0.00176

Gnomad4 AMR exome AF: 0.00984

Gnomad4 ASJ exome AF: 0.00142

Gnomad4 EAS exome AF: 0.00695

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.00955

Gnomad4 NFE exome AF: 0.00828

Gnomad4 OTH exome AF: 0.00848

GnomAD4 genome AF: 0.00624 AC: 950 AN: 152236 Hom.: 3 Cov.: 32 AF XY: 0.00594 AC XY: 442 AN XY: 74416

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00876

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0123

Gnomad4 FIN AF: 0.00869

Gnomad4 NFE AF: 0.00791

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00769 Hom.: 5

Bravo AF: 0.00589

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00839 AC: 1018

Asia WGS AF: 0.00520 AC: 19 AN: 3478

EpiCase AF: 0.00840

EpiControl AF: 0.00836

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.50	T;.;.;.;.;.
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Benign	1.4	L;L;L;.;.;.
MutationTaster	Benign	0.99	D;D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N;N;N;N;N;D
REVEL	Uncertain	0.49
Sift	Benign	0.30	T;T;T;D;D;D
Sift4G	Benign	0.26	T;T;T;D;.;D
Polyphen		0.17	B;B;P;.;.;.
Vest4		0.54
MVP		0.80
MPC		0.28
ClinPred		0.023	T
GERP RS		5.8
Varity_R		0.22
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs61752607; hg19: chr4-109086280; COSMIC: COSV54469014; COSMIC: COSV54469014;