Genetic Variant NM_001352514.2:c.*2622G>A (chr21-36751624-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001352514.2(HLCS):c.*2622G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.43 in 152,324 control chromosomes in the GnomAD database, including 14,310 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.43 ( 14295 hom., cov: 33)

Exomes 𝑓: 0.45 ( 15 hom. )

Consequence

HLCS
NM_001352514.2 3_prime_UTR

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.449

Publications

6 publications found

Variant links:

Genes affected

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

HLCS Gene-Disease associations (from GenCC):

holocarboxylase synthetase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Orphanet

HLCS links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 21-36751624-C-T is Benign according to our data. Variant chr21-36751624-C-T is described in ClinVar as Benign. ClinVar VariationId is 339920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.578 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001352514.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLCS	NM_001352514.2	MANE Select	c.*2622G>A	3_prime_UTR	Exon 11 of 11	NP_001339443.1	P50747-2
HLCS	NM_000411.8		c.*2622G>A	3_prime_UTR	Exon 12 of 12	NP_000402.3
HLCS	NM_001242784.3		c.*2622G>A	3_prime_UTR	Exon 12 of 12	NP_001229713.1	P50747-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
HLCS	ENST00000674895.3	MANE Select	c.*2622G>A	3_prime_UTR	Exon 11 of 11	ENSP00000502087.2	P50747-2
HLCS	ENST00000336648.8	TSL:1	c.*2622G>A	3_prime_UTR	Exon 12 of 12	ENSP00000338387.3	P50747-1
HLCS	ENST00000399120.5	TSL:1	c.*2622G>A	3_prime_UTR	Exon 12 of 12	ENSP00000382071.1	P50747-1

Frequencies

GnomAD3 genomes

AF:

0.430

AC:

65430

AN:

152088

Hom.:

14275

Cov.:

show subpopulations

Gnomad AFR

AF:

0.373

Gnomad AMI

AF:

0.531

Gnomad AMR

AF:

0.409

Gnomad ASJ

AF:

0.490

Gnomad EAS

AF:

0.410

Gnomad SAS

AF:

0.597

Gnomad FIN

AF:

0.411

Gnomad MID

AF:

0.516

Gnomad NFE

AF:

0.457

Gnomad OTH

AF:

0.459

GnomAD4 exome

AF:

0.449

AC:

AN:

118

Hom.:

Cov.:

AF XY:

0.471

AC XY:

AN XY:

104

show subpopulations

African (AFR)

AC:

AN:

American (AMR)

AF:

0.250

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AF:

0.700

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.432

AC:

AN:

Other (OTH)

AF:

0.250

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.430

AC:

65468

AN:

152206

Hom.:

14295

Cov.:

AF XY:

0.430

AC XY:

32014

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.373

AC:

15503

AN:

41548

American (AMR)

AF:

0.408

AC:

6244

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.490

AC:

1703

AN:

3472

East Asian (EAS)

AF:

0.410

AC:

2117

AN:

5166

South Asian (SAS)

AF:

0.596

AC:

2876

AN:

4828

European-Finnish (FIN)

AF:

0.411

AC:

4351

AN:

10586

Middle Eastern (MID)

AF:

0.524

AC:

153

AN:

292

European-Non Finnish (NFE)

AF:

0.457

AC:

31070

AN:

68000

Other (OTH)

AF:

0.459

AC:

968

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1971

3942

5913

7884

9855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

634

1268

1902

2536

3170

<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:

0.434

Hom.:

10101

Bravo

AF:

0.426

Asia WGS

AF:

0.507

AC:

1760

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Holocarboxylase synthetase deficiency (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.2

(source)

DANN

Benign

0.52

PhyloP100

-0.45

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over