rs757360400

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PVS1_ModerateBS1_SupportingBS2

The NM_001330360.2(POLA1):c.44-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000875 in 1,142,712 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.0000058 ( 0 hom. 4 hem. )

Consequence

POLA1
NM_001330360.2 splice_acceptor, intron

Scores

Splicing: ADA: 0.9970

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.80

Publications

0 publications found

Variant links:

Genes affected

POLA1 (HGNC:9173): (DNA polymerase alpha 1, catalytic subunit) This gene encodes the catalytic subunit of DNA polymerase, which together with a regulatory and two primase subunits, forms the DNA polymerase alpha complex. The catalytic subunit plays an essential role in the initiation of DNA replication. [provided by RefSeq, Mar 2010]

POLA1 Gene-Disease associations (from GenCC):

X-linked intellectual disability, van Esch type
Inheritance: XL Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
X-linked reticulate pigmentary disorder
Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet

POLA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.028363967 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.7, offset of 9, new splice context is: tcttttttcggctctgtcAGatt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000359 (4/111339) while in subpopulation AFR AF = 0.000131 (4/30607). AF 95% confidence interval is 0.0000444. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001330360.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLA1	NM_001330360.2	MANE Select	c.44-2A>G	splice_acceptor intron	N/A	NP_001317289.1	A6NMQ1
POLA1	NM_001440806.1		c.44-2A>G	splice_acceptor intron	N/A	NP_001427735.1
POLA1	NM_016937.4		c.26-2A>G	splice_acceptor intron	N/A	NP_058633.2	P09884

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
POLA1	ENST00000379068.8	TSL:5 MANE Select	c.44-2A>G	splice_acceptor intron	N/A	ENSP00000368358.3	A6NMQ1
POLA1	ENST00000379059.7	TSL:1	c.26-2A>G	splice_acceptor intron	N/A	ENSP00000368349.3	P09884
POLA1	ENST00000933044.1		c.26-2A>G	splice_acceptor intron	N/A	ENSP00000603103.1

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111339

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000131

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

GnomAD2 exomes

AF:

0.00000748

AC:

AN:

133775

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.0000951

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000582

AC:

AN:

1031373

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

321189

show subpopulations

African (AFR)

AF:

0.000250

AC:

AN:

24008

American (AMR)

AF:

0.00

AC:

AN:

26118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17370

East Asian (EAS)

AF:

0.00

AC:

AN:

29216

South Asian (SAS)

AF:

0.00

AC:

AN:

42680

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38366

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3809

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

806846

Other (OTH)

AF:

0.00

AC:

AN:

42960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

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:

0.0000359

AC:

AN:

111339

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33555

show subpopulations

African (AFR)

AF:

0.000131

AC:

AN:

30607

American (AMR)

AF:

0.00

AC:

AN:

10418

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00

AC:

AN:

2640

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5931

Middle Eastern (MID)

AF:

0.00

AC:

AN:

234

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53090

Other (OTH)

AF:

0.00

AC:

AN:

1504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.608

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0000342

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000249

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

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_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.87

CADD

Pathogenic

(source)

DANN

Benign

0.44

FATHMM_MKL

Benign

0.73

PhyloP100

3.8

GERP RS

1.4

Mutation Taster

=24/76

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Benign

0.47

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 11

DS_AL_spliceai

1.0

Position offset: 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