dbSNP rs11266792: HMGA1:p.Asp19Asp (chr6-34240837-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_145899.3(HMGA1):c.57C>T(p.Asp19Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00316 in 1,613,250 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0094 ( 18 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 35 hom. )

Consequence

HMGA1
NM_145899.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.400

Publications

1 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 links:

MIR6835 (HGNC:49963): (microRNA 6835) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR6835 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 6-34240837-C-T is Benign according to our data. Variant chr6-34240837-C-T is described in ClinVar as Benign. ClinVar VariationId is 783751.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.4 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00943 (1436/152250) while in subpopulation AFR AF = 0.026 (1081/41536). AF 95% confidence interval is 0.0247. There are 18 homozygotes in GnomAd4. There are 667 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1436 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGA1	NM_145899.3	MANE Select	c.57C>T	p.Asp19Asp	synonymous	Exon 3 of 6	NP_665906.1	P17096-1
HMGA1	NM_001319078.2		c.57C>T	p.Asp19Asp	synonymous	Exon 2 of 5	NP_001306007.1	P17096-1
HMGA1	NM_001319079.2		c.57C>T	p.Asp19Asp	synonymous	Exon 3 of 6	NP_001306008.1	P17096-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HMGA1	ENST00000311487.9	TSL:1 MANE Select	c.57C>T	p.Asp19Asp	synonymous	Exon 3 of 6	ENSP00000308227.4	P17096-1
HMGA1	ENST00000447654.5	TSL:1	c.57C>T	p.Asp19Asp	synonymous	Exon 2 of 5	ENSP00000399888.1	P17096-1
HMGA1	ENST00000347617.10	TSL:1	c.57C>T	p.Asp19Asp	synonymous	Exon 2 of 5	ENSP00000288245.9	P17096-2

Frequencies

GnomAD3 genomes

AF:

0.00943

AC:

1435

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0261

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00198

Gnomad OTH

AF:

0.0124

GnomAD2 exomes

AF:

0.00480

AC:

1202

AN:

250454

AF XY:

0.00416

show subpopulations

Gnomad AFR exome

AF:

0.0273

Gnomad AMR exome

AF:

0.00688

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000370

Gnomad NFE exome

AF:

0.00199

Gnomad OTH exome

AF:

0.00573

GnomAD4 exome

AF:

0.00250

AC:

3655

AN:

1461000

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1755

AN XY:

726802

show subpopulations

African (AFR)

AF:

0.0252

AC:

842

AN:

33460

American (AMR)

AF:

0.00704

AC:

315

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0244

AC:

638

AN:

26130

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.000580

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.000262

AC:

AN:

53386

Middle Eastern (MID)

AF:

0.00954

AC:

AN:

5240

European-Non Finnish (NFE)

AF:

0.00131

AC:

1453

AN:

1111840

Other (OTH)

AF:

0.00482

AC:

291

AN:

60318

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

209

418

626

835

1044

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

152

228

304

380

<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:

0.00943

AC:

1436

AN:

152250

Hom.:

Cov.:

AF XY:

0.00896

AC XY:

667

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0260

AC:

1081

AN:

41536

American (AMR)

AF:

0.00641

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0242

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000828

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00198

AC:

135

AN:

68028

Other (OTH)

AF:

0.0123

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

162

243

324

405

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00684

Hom.:

Bravo

AF:

0.0106

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00218

EpiControl

AF:

0.00284

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.84

PhyloP100

-0.40

Mutation Taster

=99/1

polymorphism

(source)

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

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