dbSNP rs139876191: HMGA1:c.136-15_136-14delCC (chr6-34242693-ACC-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_145899.3(HMGA1):c.136-15_136-14delCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,537,396 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: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

HMGA1
NM_145899.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.589

Publications

16 publications found

Variant links:

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)

HMGA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMGA1	NM_145899.3	MANE Select	c.136-15_136-14delCC	intron	N/A	NP_665906.1	P17096-1
HMGA1	NM_001319078.2		c.136-15_136-14delCC	intron	N/A	NP_001306007.1	P17096-1
HMGA1	NM_001319079.2		c.136-15_136-14delCC	intron	N/A	NP_001306008.1	P17096-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HMGA1	ENST00000311487.9	TSL:1 MANE Select	c.136-18_136-17delCC	intron	N/A	ENSP00000308227.4	P17096-1
HMGA1	ENST00000447654.5	TSL:1	c.136-18_136-17delCC	intron	N/A	ENSP00000399888.1	P17096-1
HMGA1	ENST00000347617.10	TSL:1	c.103-18_103-17delCC	intron	N/A	ENSP00000288245.9	P17096-2

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151834

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000144

AC:

AN:

1385562

Hom.:

AF XY:

0.00000292

AC XY:

AN XY:

685980

show subpopulations

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

African (AFR)

AF:

0.0000316

AC:

AN:

31596

American (AMR)

AF:

0.00

AC:

AN:

37336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25168

East Asian (EAS)

AF:

0.00

AC:

AN:

36664

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79904

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5110

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1062236

Other (OTH)

AF:

0.00

AC:

AN:

57484

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000132

AC:

AN:

151834

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41298

American (AMR)

AF:

0.00

AC:

AN:

15252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67960

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

-0.59

BranchPoint Hunter

2.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over