rs3741622

Variant names:

• chr12-49032195-T-C
• rs3741622
• NM_003482.4:c.12510A>G

Your query was ambiguous. Multiple possible variants found:

• chr12-49032195-T-C
• chr12-49032195-T-A

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.12510A>G​(p.Pro4170Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.339 in 1,612,274 control chromosomes in the GnomAD database, including 97,473 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6672 hom., cov: 33)
  • Exomes 𝑓: 0.35 (90801 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.643
• Publications: 27 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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, ClinGen
• 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=-0.6).
• BP6: Variant 12-49032195-T-C is Benign according to our data. Variant chr12-49032195-T-C is described in ClinVar as Benign. ClinVar VariationId is 94158.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.643 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.41 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.12510A>G	p.Pro4170Pro	synonymous	Exon 40 of 55	NP_003473.3	O14686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.12510A>G	p.Pro4170Pro	synonymous	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.12510A>G	p.Pro4170Pro	synonymous	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.12519A>G	p.Pro4173Pro	synonymous	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.267 AC: 40557 AN: 152072 Hom.: 6673 Cov.: 33

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.331

Gnomad AMR AF: 0.258

Gnomad ASJ AF: 0.219

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.423

Gnomad FIN AF: 0.358

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.350

Gnomad OTH AF: 0.262

GnomAD2 exomes AF: 0.321 AC: 79586 AN: 247818 AF XY: 0.332

Gnomad AFR exome AF: 0.0641

Gnomad AMR exome AF: 0.231

Gnomad ASJ exome AF: 0.228

Gnomad EAS exome AF: 0.437

Gnomad FIN exome AF: 0.364

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.347 AC: 506210 AN: 1460084 Hom.: 90801 Cov.: 66 AF XY: 0.349 AC XY: 253160 AN XY: 726044

African (AFR) AF: 0.0579 AC: 1937 AN: 33446

American (AMR) AF: 0.233 AC: 10419 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 6048 AN: 26072

East Asian (EAS) AF: 0.398 AC: 15777 AN: 39644

South Asian (SAS) AF: 0.396 AC: 34131 AN: 86222

European-Finnish (FIN) AF: 0.365 AC: 19461 AN: 53270

Middle Eastern (MID) AF: 0.233 AC: 1343 AN: 5756

European-Non Finnish (NFE) AF: 0.357 AC: 397017 AN: 1110758

Other (OTH) AF: 0.333 AC: 20077 AN: 60260

GnomAD4 genome AF: 0.267 AC: 40560 AN: 152190 Hom.: 6672 Cov.: 33 AF XY: 0.270 AC XY: 20067 AN XY: 74398

African (AFR) AF: 0.0754 AC: 3133 AN: 41552

American (AMR) AF: 0.258 AC: 3944 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.219 AC: 760 AN: 3468

East Asian (EAS) AF: 0.425 AC: 2189 AN: 5156

South Asian (SAS) AF: 0.424 AC: 2043 AN: 4820

European-Finnish (FIN) AF: 0.358 AC: 3793 AN: 10596

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.350 AC: 23783 AN: 67988

Other (OTH) AF: 0.262 AC: 554 AN: 2114

Alfa AF: 0.311 Hom.: 3690

Bravo AF: 0.246

Asia WGS AF: 0.387 AC: 1345 AN: 3478

EpiCase AF: 0.340

EpiControl AF: 0.334

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	1	Kabuki syndrome (1)
-	-	1	Kabuki syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.8
DANN	Benign	0.63
PhyloP100		0.64
Mutation Taster		=100/0	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: rs3741622; hg19: chr12-49425978; COSMIC: COSV56407671; COSMIC: COSV56407671;