chr18-6080904-A-G

Variant names:

• chr18-6080904-A-G
• rs138175239
• NM_001330559.2:c.1421T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001330559.2(L3MBTL4):​c.1421T>C​(p.Ile474Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,608,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000025 (0 hom.)
• Consequence: L3MBTL4 NM_001330559.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.497
• Publications: 0 publications found

Genes affected

L3MBTL4 (HGNC:26677): (L3MBTL histone methyl-lysine binding protein 4) Predicted to enable chromatin binding activity and histone binding activity. Predicted to be involved in negative regulation of transcription, DNA-templated. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000266846 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03752458).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
L3MBTL4	NM_001330559.2	c.1421T>C	p.Ile474Thr	missense_variant	Exon 16 of 19	ENST00000317931.12	NP_001317488.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
L3MBTL4	ENST00000317931.12	c.1421T>C	p.Ile474Thr	missense_variant	Exon 16 of 19	5	NM_001330559.2	ENSP00000318543.7

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000285 AC: 7 AN: 245816 AF XY: 0.0000452

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000270

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000247 AC: 36 AN: 1456180 Hom.: 0 Cov.: 28 AF XY: 0.0000345 AC XY: 25 AN XY: 724086

African (AFR) AF: 0.00 AC: 0 AN: 33398

American (AMR) AF: 0.00 AC: 0 AN: 44422

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25992

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85300

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4588

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1109570

Other (OTH) AF: 0.0000499 AC: 3 AN: 60118

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41456

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

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

Dec 01, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1421T>C (p.I474T) alteration is located in exon 16 (coding exon 14) of the L3MBTL4 gene. This alteration results from a T to C substitution at nucleotide position 1421, causing the isoleucine (I) at amino acid position 474 to be replaced by a threonine (T). 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	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.8
DANN	Benign	0.75
DEOGEN2	Benign	0.014	T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.63	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.038	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.49	N;.;N
PhyloP100		0.50
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.51	N;N;N
REVEL	Benign	0.096
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.63	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.12
MVP		0.13
ClinPred		0.030	T
GERP RS		-5.3
Varity_R		0.049
gMVP		0.12
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs138175239; hg19: chr18-6080903;