6-34243461-C-T

Variant names:

• chr6-34243461-C-T
• rs41269028
• NM_145899.3:c.220-7C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_145899.3(HMGA1):​c.220-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0382 in 1,610,404 control chromosomes in the GnomAD database, including 1,417 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.027 (80 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1337 hom.)
• Consequence: HMGA1 NM_145899.3 splice_region, intron
• Scores: Splicing: ADA: 0.00005694
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.268
• Publications: 11 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)

ENSG00000295821 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0273 (4153/152106) while in subpopulation NFE AF = 0.0418 (2841/68014). AF 95% confidence interval is 0.0405. There are 80 homozygotes in GnomAd4. There are 1968 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4153 AD gene.

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.220-7C>T		splice_region intron	N/A	NP_665906.1	P17096-1
	HMGA1	NM_001319078.2		c.220-7C>T		splice_region intron	N/A	NP_001306007.1	P17096-1
	HMGA1	NM_001319079.2		c.220-7C>T		splice_region 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.220-7C>T		splice_region intron	N/A	ENSP00000308227.4	P17096-1
	HMGA1	ENST00000447654.5	TSL:1	c.220-7C>T		splice_region intron	N/A	ENSP00000399888.1	P17096-1
	HMGA1	ENST00000347617.10	TSL:1	c.187-7C>T		splice_region intron	N/A	ENSP00000288245.9	P17096-2

Frequencies

GnomAD3 genomes AF: 0.0273 AC: 4152 AN: 151988 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00758

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0191

Gnomad ASJ AF: 0.0721

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0260

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0418

Gnomad OTH AF: 0.0187

GnomAD2 exomes AF: 0.0283 AC: 7102 AN: 250856 AF XY: 0.0282

Gnomad AFR exome AF: 0.00723

Gnomad AMR exome AF: 0.0169

Gnomad ASJ exome AF: 0.0661

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0395

Gnomad OTH exome AF: 0.0294

GnomAD4 exome AF: 0.0393 AC: 57293 AN: 1458298 Hom.: 1337 Cov.: 31 AF XY: 0.0383 AC XY: 27799 AN XY: 725654

African (AFR) AF: 0.00557 AC: 186 AN: 33422

American (AMR) AF: 0.0169 AC: 756 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.0649 AC: 1694 AN: 26108

East Asian (EAS) AF: 0.000378 AC: 15 AN: 39674

South Asian (SAS) AF: 0.0170 AC: 1468 AN: 86184

European-Finnish (FIN) AF: 0.0266 AC: 1418 AN: 53400

Middle Eastern (MID) AF: 0.00669 AC: 38 AN: 5682

European-Non Finnish (NFE) AF: 0.0446 AC: 49404 AN: 1108882

Other (OTH) AF: 0.0384 AC: 2314 AN: 60272

GnomAD4 genome AF: 0.0273 AC: 4153 AN: 152106 Hom.: 80 Cov.: 32 AF XY: 0.0265 AC XY: 1968 AN XY: 74378

African (AFR) AF: 0.00755 AC: 313 AN: 41430

American (AMR) AF: 0.0190 AC: 290 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0721 AC: 250 AN: 3468

East Asian (EAS) AF: 0.00174 AC: 9 AN: 5176

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4824

European-Finnish (FIN) AF: 0.0260 AC: 276 AN: 10604

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0418 AC: 2841 AN: 68014

Other (OTH) AF: 0.0185 AC: 39 AN: 2108

Alfa AF: 0.0358 Hom.: 106

Bravo AF: 0.0254

Asia WGS AF: 0.0180 AC: 65 AN: 3478

EpiCase AF: 0.0358

EpiControl AF: 0.0345

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.3
DANN	Benign	0.72
PhyloP100		-0.27
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000057
dbscSNV1_RF	Benign	0.058
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: rs41269028; hg19: chr6-34211238;