Genetic Variant L3MBTL4:p.Ser400Arg (chr18-6093528-A-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001330559.2(L3MBTL4):c.1200T>G(p.Ser400Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

L3MBTL4
NM_001330559.2 missense, splice_region

Scores

Splicing: ADA: 0.0009020

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0770

Publications

0 publications found

Variant links:

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]

L3MBTL4 links:

ENSG00000266846 (HGNC:):

ENSG00000266846 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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
L3MBTL4	NM_001330559.2 link	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	Exon 15 of 19	ENST00000317931.12	NP_001317488.1	F8W9S8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
L3MBTL4	ENST00000317931.12 link	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	Exon 15 of 19	5	NM_001330559.2	ENSP00000318543.7	F8W9S8
L3MBTL4	ENST00000400104.7 link	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	Exon 15 of 17	1		ENSP00000382975.3	Q8NA19-2
L3MBTL4	ENST00000400105.6 link	c.1200T>G	p.Ser400Arg	missense_variant, splice_region_variant	Exon 15 of 20	2		ENSP00000382976.2	Q8NA19-1
ENSG00000266846	ENST00000659442.1 link	n.1423+4178A>C		intron_variant	Intron 7 of 7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725424

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.00

AC:

AN:

44004

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25980

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

85382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111076

Other (OTH)

AF:

0.0000166

AC:

AN:

60222

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 02, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1200T>G (p.S400R) alteration is located in exon 15 (coding exon 13) of the L3MBTL4 gene. This alteration results from a T to G substitution at nucleotide position 1200, causing the serine (S) at amino acid position 400 to be replaced by an arginine (R). 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

Pathogenic

0.96

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

T;T;.

Eigen

Benign

0.10

Eigen_PC

Benign

0.057

FATHMM_MKL

Benign

0.43

LIST_S2

Uncertain

0.90

D;T;D

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

L;.;L

PhyloP100

0.077

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-3.2

D;D;D

REVEL

Uncertain

0.31

Sift

Benign

0.066

T;T;T

Sift4G

Benign

0.088

T;T;D

Polyphen

1.0

D;P;.

Vest4

0.54

MutPred

0.66

Loss of glycosylation at S400 (P = 0.0229);Loss of glycosylation at S400 (P = 0.0229);Loss of glycosylation at S400 (P = 0.0229);

MVP

0.48

ClinPred

0.94

GERP RS

1.5

Varity_R

0.25

gMVP

0.58

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00090

dbscSNV1_RF

Benign

0.41

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over