12-49050898-G-A

Variant names:

• chr12-49050898-G-A
• rs745396055
• NM_003482.4:c.2785C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003482.4(KMT2D):​c.2785C>T​(p.Leu929Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,384,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000058 (0 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.97
• Publications: 0 publications found

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

KMT2D Gene-Disease associations (from GenCC):

• choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Kabuki syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 12-49050898-G-A is Benign according to our data. Variant chr12-49050898-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259056.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.97 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.2785C>T	p.Leu929Leu	synonymous_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.2785C>T	p.Leu929Leu	synonymous_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.2785C>T	p.Leu929Leu	synonymous_variant	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.2785C>T	p.Leu929Leu	synonymous_variant	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.2785C>T	p.Leu929Leu	synonymous_variant	Exon 10 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000155 AC: 3 AN: 193134 AF XY: 0.0000293

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000121

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000578 AC: 8 AN: 1384800 Hom.: 0 Cov.: 35 AF XY: 0.00000736 AC XY: 5 AN XY: 679730

African (AFR) AF: 0.00 AC: 0 AN: 31136

American (AMR) AF: 0.00 AC: 0 AN: 34772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21094

East Asian (EAS) AF: 0.0000257 AC: 1 AN: 38926

South Asian (SAS) AF: 0.00 AC: 0 AN: 74198

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50548

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5390

European-Non Finnish (NFE) AF: 0.00000560 AC: 6 AN: 1071808

Other (OTH) AF: 0.0000176 AC: 1 AN: 56928

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome Benign:1

Nov 02, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome;CN030661:Kabuki syndrome 1 Benign:1

Jun 09, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	8.3
DANN	Benign	0.74
PhyloP100		3.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs745396055; hg19: chr12-49444681;