chr15-37094545-A-G

Variant names:

• chr15-37094545-A-G
• rs137952617
• NM_170675.5:c.471T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_170675.5(MEIS2):​c.471T>C​(p.His157His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,613,150 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: 𝑓 0.00025 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00040 (0 hom.)
• Consequence: MEIS2 NM_170675.5 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.636
• Publications: 0 publications found

Genes affected

MEIS2 (HGNC:7001): (Meis homeobox 2) This gene encodes a homeobox protein belonging to the TALE ('three amino acid loop extension') family of homeodomain-containing proteins. TALE homeobox proteins are highly conserved transcription regulators, and several members have been shown to be essential contributors to developmental programs. Multiple transcript variants encoding distinct isoforms have been described for this gene. [provided by RefSeq, Jul 2008]

MEIS2 Gene-Disease associations (from GenCC):

• cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, Ambry Genetics
• syndromic intellectual disability

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: STRONG Submitted by: G2P

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 15-37094545-A-G is Benign according to our data. Variant chr15-37094545-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 532738.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 38 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170675.5. 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
	MEIS2	NM_170675.5	MANE Select	c.471T>C	p.His157His	synonymous	Exon 5 of 12	NP_733775.1	O14770-1
	MEIS2	NM_001220482.2		c.471T>C	p.His157His	synonymous	Exon 6 of 13	NP_001207411.1	O14770-4
	MEIS2	NM_170676.5		c.471T>C	p.His157His	synonymous	Exon 5 of 12	NP_733776.1	O14770-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MEIS2	ENST00000561208.6	TSL:1 MANE Select	c.471T>C	p.His157His	synonymous	Exon 5 of 12	ENSP00000453793.1	O14770-1
	MEIS2	ENST00000338564.9	TSL:1	c.471T>C	p.His157His	synonymous	Exon 6 of 13	ENSP00000341400.4	O14770-4
	MEIS2	ENST00000424352.6	TSL:1	c.471T>C	p.His157His	synonymous	Exon 5 of 13	ENSP00000404185.2	O14770-2

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152186 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000269 AC: 67 AN: 249494 AF XY: 0.000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000362

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000397 AC: 580 AN: 1460846 Hom.: 0 Cov.: 30 AF XY: 0.000398 AC XY: 289 AN XY: 726664

African (AFR) AF: 0.0000299 AC: 1 AN: 33452

American (AMR) AF: 0.0000449 AC: 2 AN: 44564

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000662 AC: 57 AN: 86050

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.000450 AC: 500 AN: 1111564

Other (OTH) AF: 0.000331 AC: 20 AN: 60360

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152304 Hom.: 0 Cov.: 30 AF XY: 0.000188 AC XY: 14 AN XY: 74474

African (AFR) AF: 0.000120 AC: 5 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000412 AC: 28 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000327 Hom.: 0

Bravo AF: 0.000185

EpiCase AF: 0.000273

EpiControl AF: 0.000416

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies (1)
-	-	1	MEIS2-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
CADD	Benign	9.0
DANN	Benign	0.74
PhyloP100		0.64
PromoterAI		-0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs137952617; hg19: chr15-37386746;