6-34242693-ACC-AC

Variant names:

• chr6-34242693-AC-A
• rs139876191
• NM_145899.3:c.136-14delC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145899.3(HMGA1):​c.136-14delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,385,560 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: HMGA1 NM_145899.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.772
• Publications: 0 publications found

Genes affected

HMGA1 (HGNC:5010): (high mobility group AT-hook 1) This gene encodes a chromatin-associated protein involved in the regulation of gene transcription, integration of retroviruses into chromosomes, and the metastatic progression of cancer cells. The encoded protein preferentially binds to the minor groove of AT-rich regions in double-stranded DNA. Multiple transcript variants encoding different isoforms have been found for this gene. Pseudogenes of this gene have been identified on multiple chromosomes. [provided by RefSeq, Jan 2016]

HMGA1 Gene-Disease associations (from GenCC):

• type 2 diabetes mellitus

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145899.3. 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
	HMGA1	NM_145899.3	MANE Select	c.136-14delC		intron	N/A	NP_665906.1	P17096-1
	HMGA1	NM_001319078.2		c.136-14delC		intron	N/A	NP_001306007.1	P17096-1
	HMGA1	NM_001319079.2		c.136-14delC		intron	N/A	NP_001306008.1	P17096-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA1	ENST00000311487.9	TSL:1 MANE Select	c.136-18delC		intron	N/A	ENSP00000308227.4	P17096-1
	HMGA1	ENST00000447654.5	TSL:1	c.136-18delC		intron	N/A	ENSP00000399888.1	P17096-1
	HMGA1	ENST00000347617.10	TSL:1	c.103-18delC		intron	N/A	ENSP00000288245.9	P17096-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1385560 Hom.: 0 Cov.: 28 AF XY: 0.00000292 AC XY: 2 AN XY: 685978

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 37336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25168

East Asian (EAS) AF: 0.00 AC: 0 AN: 36664

South Asian (SAS) AF: 0.00 AC: 0 AN: 79902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50064

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5110

European-Non Finnish (NFE) AF: 0.00000282 AC: 3 AN: 1062236

Other (OTH) AF: 0.00 AC: 0 AN: 57484

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.77
BranchPoint Hunter		2.0

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: rs139876191; hg19: chr6-34210470;