NM_001388492.1:c.6591G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001388492.1(HTT):c.6591G>A(p.Glu2197Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.299 in 1,613,220 control chromosomes in the GnomAD database, including 74,997 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.26 ( 6032 hom., cov: 33)

Exomes 𝑓: 0.30 ( 68965 hom. )

Consequence

HTT
NM_001388492.1 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0900

Publications

19 publications found

Variant links:

Genes affected

HTT (HGNC:4851): (huntingtin) Huntingtin is a disease gene linked to Huntington's disease, a neurodegenerative disorder characterized by loss of striatal neurons. This is thought to be caused by an expanded, unstable trinucleotide repeat in the huntingtin gene, which translates as a polyglutamine repeat in the protein product. A fairly broad range of trinucleotide repeats (9-35) has been identified in normal controls, and repeat numbers in excess of 40 have been described as pathological. The huntingtin locus is large, spanning 180 kb and consisting of 67 exons. The huntingtin gene is widely expressed and is required for normal development. It is expressed as 2 alternatively polyadenylated forms displaying different relative abundance in various fetal and adult tissues. The larger transcript is approximately 13.7 kb and is expressed predominantly in adult and fetal brain whereas the smaller transcript of approximately 10.3 kb is more widely expressed. The genetic defect leading to Huntington's disease may not necessarily eliminate transcription, but may confer a new property on the mRNA or alter the function of the protein. One candidate is the huntingtin-associated protein-1, highly expressed in brain, which has increased affinity for huntingtin protein with expanded polyglutamine repeats. This gene contains an upstream open reading frame in the 5' UTR that inhibits expression of the huntingtin gene product through translational repression. [provided by RefSeq, Jul 2016]

HTT Gene-Disease associations (from GenCC):

Huntington disease
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
Lopes-Maciel-Rodan syndrome
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
juvenile Huntington disease
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

HTT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 4-3212105-G-A is Benign according to our data. Variant chr4-3212105-G-A is described in ClinVar as Benign. ClinVar VariationId is 1599468.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.09 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.376 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HTT	NM_001388492.1 link	c.6591G>A	p.Glu2197Glu	synonymous_variant	Exon 48 of 67	ENST00000355072.11	NP_001375421.1
HTT	NM_002111.8 link	c.6591G>A	p.Glu2197Glu	synonymous_variant	Exon 48 of 67		NP_002102.4	P42858

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HTT	ENST00000355072.11 link	c.6591G>A	p.Glu2197Glu	synonymous_variant	Exon 48 of 67	1	NM_001388492.1	ENSP00000347184.5		P42858

Frequencies

GnomAD3 genomes

AF:

0.265

AC:

40291

AN:

152050

Hom.:

6028

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.230

Gnomad AMR

AF:

0.261

Gnomad ASJ

AF:

0.306

Gnomad EAS

AF:

0.391

Gnomad SAS

AF:

0.193

Gnomad FIN

AF:

0.441

Gnomad MID

AF:

0.142

Gnomad NFE

AF:

0.307

Gnomad OTH

AF:

0.225

GnomAD2 exomes

AF:

0.295

AC:

73558

AN:

249314

AF XY:

0.289

show subpopulations

Gnomad AFR exome

AF:

0.138

Gnomad AMR exome

AF:

0.295

Gnomad ASJ exome

AF:

0.300

Gnomad EAS exome

AF:

0.391

Gnomad FIN exome

AF:

0.436

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.290

GnomAD4 exome

AF:

0.303

AC:

442319

AN:

1461052

Hom.:

68965

Cov.:

AF XY:

0.299

AC XY:

217239

AN XY:

726770

show subpopulations

African (AFR)

AF:

0.131

AC:

4397

AN:

33470

American (AMR)

AF:

0.288

AC:

12861

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.300

AC:

7836

AN:

26132

East Asian (EAS)

AF:

0.385

AC:

15266

AN:

39680

South Asian (SAS)

AF:

0.190

AC:

16363

AN:

86240

European-Finnish (FIN)

AF:

0.426

AC:

22747

AN:

53364

Middle Eastern (MID)

AF:

0.130

AC:

748

AN:

5758

European-Non Finnish (NFE)

AF:

0.310

AC:

344696

AN:

1111334

Other (OTH)

AF:

0.288

AC:

17405

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

15788

31577

47365

63154

78942

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11342

22684

34026

45368

56710

<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:

0.265

AC:

40307

AN:

152168

Hom.:

6032

Cov.:

AF XY:

0.266

AC XY:

19769

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.146

AC:

6046

AN:

41526

American (AMR)

AF:

0.261

AC:

3987

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.306

AC:

1063

AN:

3470

East Asian (EAS)

AF:

0.390

AC:

2020

AN:

5180

South Asian (SAS)

AF:

0.192

AC:

926

AN:

4824

European-Finnish (FIN)

AF:

0.441

AC:

4663

AN:

10570

Middle Eastern (MID)

AF:

0.150

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.307

AC:

20859

AN:

68002

Other (OTH)

AF:

0.232

AC:

490

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1494

2987

4481

5974

7468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

424

848

1272

1696

2120

<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:

0.283

Hom.:

2993

Bravo

AF:

0.248

Asia WGS

AF:

0.313

AC:

1088

AN:

3478

EpiCase

AF:

0.293

EpiControl

AF:

0.289

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.61

(source)

DANN

Benign

0.26

PhyloP100

0.090

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over