NM_145899.3:c.136-14dupC

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_145899.3(HMGA1):​c.136-14dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0376 in 1,537,206 control chromosomes in the GnomAD database, including 2,965 homozygotes. Variant has been reported in ClinVar as Benign (★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.054 (483 hom., cov: 31)
  • Exomes 𝑓: 0.036 (2482 hom.)
• Consequence: HMGA1 NM_145899.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.772
• Publications: 16 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 6-34242693-A-AC is Benign according to our data. Variant chr6-34242693-A-AC is described in ClinVar as Benign. ClinVar VariationId is 1277118.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

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.136-14dupC		intron	N/A	NP_665906.1	P17096-1
	HMGA1	NM_001319078.2		c.136-14dupC		intron	N/A	NP_001306007.1	P17096-1
	HMGA1	NM_001319079.2		c.136-14dupC		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.136-19_136-18insC		intron	N/A	ENSP00000308227.4	P17096-1
	HMGA1	ENST00000447654.5	TSL:1	c.136-19_136-18insC		intron	N/A	ENSP00000399888.1	P17096-1
	HMGA1	ENST00000347617.10	TSL:1	c.103-19_103-18insC		intron	N/A	ENSP00000288245.9	P17096-2

Frequencies

GnomAD3 genomes AF: 0.0539 AC: 8188 AN: 151818 Hom.: 473 Cov.: 31

Gnomad AFR AF: 0.0562

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0540

Gnomad EAS AF: 0.100

Gnomad SAS AF: 0.0334

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0263

Gnomad OTH AF: 0.0647

GnomAD2 exomes AF: 0.0774 AC: 13344 AN: 172502 AF XY: 0.0678

Gnomad AFR exome AF: 0.0528

Gnomad AMR exome AF: 0.298

Gnomad ASJ exome AF: 0.0445

Gnomad EAS exome AF: 0.0960

Gnomad FIN exome AF: 0.0180

Gnomad NFE exome AF: 0.0270

Gnomad OTH exome AF: 0.0625

GnomAD4 exome AF: 0.0358 AC: 49586 AN: 1385270 Hom.: 2482 Cov.: 28 AF XY: 0.0352 AC XY: 24167 AN XY: 685858

African (AFR) AF: 0.0540 AC: 1706 AN: 31590

American (AMR) AF: 0.280 AC: 10433 AN: 37316

Ashkenazi Jewish (ASJ) AF: 0.0469 AC: 1179 AN: 25162

East Asian (EAS) AF: 0.107 AC: 3929 AN: 36660

South Asian (SAS) AF: 0.0351 AC: 2802 AN: 79896

European-Finnish (FIN) AF: 0.0178 AC: 890 AN: 50062

Middle Eastern (MID) AF: 0.0603 AC: 308 AN: 5104

European-Non Finnish (NFE) AF: 0.0244 AC: 25860 AN: 1062006

Other (OTH) AF: 0.0431 AC: 2479 AN: 57474

GnomAD4 genome AF: 0.0540 AC: 8211 AN: 151936 Hom.: 483 Cov.: 31 AF XY: 0.0552 AC XY: 4097 AN XY: 74260

African (AFR) AF: 0.0561 AC: 2324 AN: 41412

American (AMR) AF: 0.186 AC: 2847 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0540 AC: 187 AN: 3462

East Asian (EAS) AF: 0.0997 AC: 514 AN: 5156

South Asian (SAS) AF: 0.0333 AC: 160 AN: 4810

European-Finnish (FIN) AF: 0.0156 AC: 165 AN: 10564

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0263 AC: 1788 AN: 67950

Other (OTH) AF: 0.0650 AC: 137 AN: 2108

Alfa AF: 0.0216 Hom.: 16

Bravo AF: 0.0704

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	-	Diabetes mellitus type 2, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.77
BranchPoint Hunter		2.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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;