ENST00000478214.1:n.531A>C

Variant names:

• chr6-34244966-A-C
• rs2780219
• ENST00000478214.1:n.531A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000478214.1(HMGA1):​n.531A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00095 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HMGA1 ENST00000478214.1 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.68
• Publications: 12 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.019).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000478214.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA1	NM_145899.3	MANE Select	c.*82A>C		3_prime_UTR	Exon 6 of 6	NP_665906.1
	HMGA1	NM_001319078.2		c.*82A>C		3_prime_UTR	Exon 5 of 5	NP_001306007.1
	HMGA1	NM_001319079.2		c.*82A>C		3_prime_UTR	Exon 6 of 6	NP_001306008.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HMGA1	ENST00000478214.1	TSL:1	n.531A>C		non_coding_transcript_exon	Exon 5 of 5
	HMGA1	ENST00000311487.9	TSL:1 MANE Select	c.*82A>C		3_prime_UTR	Exon 6 of 6	ENSP00000308227.4
	HMGA1	ENST00000447654.5	TSL:1	c.*82A>C		3_prime_UTR	Exon 5 of 5	ENSP00000399888.1

Frequencies

GnomAD3 genomes AF: 0.000934 AC: 136 AN: 145542 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.000874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000821

Gnomad ASJ AF: 0.000874

Gnomad EAS AF: 0.00167

Gnomad SAS AF: 0.00175

Gnomad FIN AF: 0.00134

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000844

Gnomad OTH AF: 0.00100

GnomAD2 exomes AF: 0.00210 AC: 313 AN: 148880 AF XY: 0.00175

Gnomad AFR exome AF: 0.00193

Gnomad AMR exome AF: 0.00529

Gnomad ASJ exome AF: 0.00282

Gnomad EAS exome AF: 0.000636

Gnomad FIN exome AF: 0.000396

Gnomad NFE exome AF: 0.00169

Gnomad OTH exome AF: 0.00549

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00409 AC: 5455 AN: 1334044 Hom.: 0 Cov.: 25 AF XY: 0.00381 AC XY: 2513 AN XY: 659696

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00449 AC: 135 AN: 30070

American (AMR) AF: 0.00594 AC: 201 AN: 33822

Ashkenazi Jewish (ASJ) AF: 0.00222 AC: 54 AN: 24328

East Asian (EAS) AF: 0.00130 AC: 45 AN: 34748

South Asian (SAS) AF: 0.00144 AC: 112 AN: 77768

European-Finnish (FIN) AF: 0.000295 AC: 14 AN: 47418

Middle Eastern (MID) AF: 0.00316 AC: 13 AN: 4120

European-Non Finnish (NFE) AF: 0.00457 AC: 4689 AN: 1026538

Other (OTH) AF: 0.00348 AC: 192 AN: 55232

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000947 AC: 138 AN: 145656 Hom.: 0 Cov.: 20 AF XY: 0.000932 AC XY: 66 AN XY: 70814

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000897 AC: 35 AN: 39030

American (AMR) AF: 0.000820 AC: 12 AN: 14638

Ashkenazi Jewish (ASJ) AF: 0.000874 AC: 3 AN: 3432

East Asian (EAS) AF: 0.00167 AC: 8 AN: 4778

South Asian (SAS) AF: 0.00197 AC: 9 AN: 4570

European-Finnish (FIN) AF: 0.00134 AC: 13 AN: 9676

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000844 AC: 56 AN: 66350

Other (OTH) AF: 0.000991 AC: 2 AN: 2018

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00851 Hom.: 7571

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.15
DANN	Benign	0.92
PhyloP100		-1.7
Mutation Taster		=98/2	polymorphism

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: rs2780219; hg19: chr6-34212743; COSMIC: COSV105143077; COSMIC: COSV105143077;