6-34242693-ACC-ACCC

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HMGA1	NM_145899.3	c.136-14dupC		intron_variant	Intron 3 of 5	ENST00000311487.9	NP_665906.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HMGA1	ENST00000311487.9	c.136-19_136-18insC		intron_variant	Intron 3 of 5	1	NM_145899.3	ENSP00000308227.4

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

GnomAD3 exomes AF: 0.0774 AC: 13344 AN: 172502 Hom.: 1475 AF XY: 0.0678 AC XY: 6205 AN XY: 91530

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 SAS exome AF: 0.0346

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

Gnomad4 AFR exome AF: 0.0540

Gnomad4 AMR exome AF: 0.280

Gnomad4 ASJ exome AF: 0.0469

Gnomad4 EAS exome AF: 0.107

Gnomad4 SAS exome AF: 0.0351

Gnomad4 FIN exome AF: 0.0178

Gnomad4 NFE exome AF: 0.0244

Gnomad4 OTH exome AF: 0.0431

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

Gnomad4 AFR AF: 0.0561

Gnomad4 AMR AF: 0.186

Gnomad4 ASJ AF: 0.0540

Gnomad4 EAS AF: 0.0997

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0263

Gnomad4 OTH AF: 0.0650

Bravo AF: 0.0704

Asia WGS AF: 0.0700 AC: 242 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 19, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24148075, 26296198, 23512162, 22411136, 22210315, 21364139) -

Diabetes mellitus type 2, susceptibility to Other:1

Mar 02, 2011

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		2.0

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

Publications

LitVar

Other links and lift over

dbSNP: rs139876191; hg19: chr6-34210470;