NM_003482.4:c.10671A>G

Variant names:

• chr12-49034136-T-C
• rs61942218
• NM_003482.4:c.10671A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003482.4(KMT2D):​c.10671A>G​(p.Pro3557Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0594 in 1,613,254 control chromosomes in the GnomAD database, including 3,267 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (174 hom., cov: 32)
  • Exomes 𝑓: 0.061 (3093 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.90
• Publications: 6 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-49034136-T-C is Benign according to our data. Variant chr12-49034136-T-C is described in ClinVar as Benign. ClinVar VariationId is 94138.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.9 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0616 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.10671A>G	p.Pro3557Pro	synonymous	Exon 39 of 55	NP_003473.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.10671A>G	p.Pro3557Pro	synonymous	Exon 39 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.10671A>G	p.Pro3557Pro	synonymous	Exon 39 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.10680A>G	p.Pro3560Pro	synonymous	Exon 38 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6436 AN: 152154 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0427

Gnomad ASJ AF: 0.0757

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0435

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0631

Gnomad OTH AF: 0.0468

GnomAD2 exomes AF: 0.0462 AC: 11489 AN: 248740 AF XY: 0.0463

Gnomad AFR exome AF: 0.00988

Gnomad AMR exome AF: 0.0366

Gnomad ASJ exome AF: 0.0826

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.0451

Gnomad NFE exome AF: 0.0655

Gnomad OTH exome AF: 0.0630

GnomAD4 exome AF: 0.0612 AC: 89441 AN: 1460982 Hom.: 3093 Cov.: 34 AF XY: 0.0599 AC XY: 43500 AN XY: 726788

African (AFR) AF: 0.00995 AC: 333 AN: 33478

American (AMR) AF: 0.0393 AC: 1757 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 2086 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39700

South Asian (SAS) AF: 0.0172 AC: 1480 AN: 86258

European-Finnish (FIN) AF: 0.0458 AC: 2414 AN: 52706

Middle Eastern (MID) AF: 0.0224 AC: 129 AN: 5768

European-Non Finnish (NFE) AF: 0.0701 AC: 77887 AN: 1111850

Other (OTH) AF: 0.0555 AC: 3351 AN: 60364

GnomAD4 genome AF: 0.0423 AC: 6437 AN: 152272 Hom.: 174 Cov.: 32 AF XY: 0.0412 AC XY: 3066 AN XY: 74462

African (AFR) AF: 0.0118 AC: 491 AN: 41562

American (AMR) AF: 0.0426 AC: 652 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0757 AC: 263 AN: 3472

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5170

South Asian (SAS) AF: 0.0130 AC: 63 AN: 4828

European-Finnish (FIN) AF: 0.0435 AC: 462 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0631 AC: 4294 AN: 68006

Other (OTH) AF: 0.0464 AC: 98 AN: 2114

Alfa AF: 0.0548 Hom.: 186

Bravo AF: 0.0431

Asia WGS AF: 0.00635 AC: 22 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Jul 20, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Kabuki syndrome Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.59
DANN	Benign	0.58
PhyloP100		-3.9
PromoterAI		0.18	Neutral
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs61942218; hg19: chr12-49427919; COSMIC: COSV56419845;