rs373373098

Variant names:

• chr12-49049769-G-A
• rs373373098
• NM_003482.4:c.3819C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49049769-G-A
• chr12-49049769-G-C
• chr12-49049769-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003482.4(KMT2D):​c.3819C>T​(p.Cys1273Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000417 in 1,613,414 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (6 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.72

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 12-49049769-G-A is Benign according to our data. Variant chr12-49049769-G-A is described in ClinVar as [Benign]. Clinvar id is 259057.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49049769-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.72 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000315 (48/152300) while in subpopulation SAS AF= 0.00892 (43/4822). AF 95% confidence interval is 0.0068. There are 1 homozygotes in gnomad4. There are 38 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.3819C>T	p.Cys1273Cys	synonymous_variant	Exon 12 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.3819C>T	p.Cys1273Cys	synonymous_variant	Exon 12 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.3819C>T	p.Cys1273Cys	synonymous_variant	Exon 12 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.3819C>T	p.Cys1273Cys	synonymous_variant	Exon 11 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.3819C>T	p.Cys1273Cys	synonymous_variant	Exon 11 of 54			ENSP00000509666.1

Frequencies

GnomAD3 genomes AF: 0.000309 AC: 47 AN: 152182 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00891

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000904 AC: 225 AN: 248902 Hom.: 2 AF XY: 0.00116 AC XY: 156 AN XY: 135014

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.00716

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.000331

GnomAD4 exome AF: 0.000427 AC: 624 AN: 1461114 Hom.: 6 Cov.: 34 AF XY: 0.000604 AC XY: 439 AN XY: 726736

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00656

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000126

Gnomad4 OTH exome AF: 0.000630

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152300 Hom.: 1 Cov.: 32 AF XY: 0.000510 AC XY: 38 AN XY: 74474

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00892

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000654 Hom.: 0

Bravo AF: 0.0000793

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome Benign:1

Nov 26, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Aug 26, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KMT2D-related disorder Benign:1

May 23, 2022

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	10
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs373373098; hg19: chr12-49443552;