Genetic Variant NM_014656.3:c.-134+94G>T (chr1-175166468-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014656.3(KIAA0040):c.-134+94G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 152,190 control chromosomes in the GnomAD database, including 1,396 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.12 ( 1396 hom., cov: 32)

Exomes 𝑓: 0.067 ( 0 hom. )

Consequence

KIAA0040
NM_014656.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.188

Publications

7 publications found

Variant links:

Genes affected

KIAA0040 (HGNC:28950): (KIAA0040) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

KIAA0040 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.298 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014656.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KIAA0040	NM_014656.3	MANE Select	c.-134+94G>T	intron	N/A	NP_055471.2
KIAA0040	NM_001162893.2		c.-134+94G>T	intron	N/A	NP_001156365.1
KIAA0040	NM_001162894.2		c.-134+94G>T	intron	N/A	NP_001156366.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
KIAA0040	ENST00000423313.6	TSL:1 MANE Select	c.-134+94G>T	intron	N/A	ENSP00000462172.1
KIAA0040	ENST00000444639.5	TSL:1	c.-134+94G>T	intron	N/A	ENSP00000463734.1
KIAA0040	ENST00000545251.6	TSL:1	c.-134+94G>T	intron	N/A	ENSP00000464040.1

Frequencies

GnomAD3 genomes

AF:

0.117

AC:

17724

AN:

152042

Hom.:

1395

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0271

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0919

Gnomad ASJ

AF:

0.153

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.256

Gnomad FIN

AF:

0.157

Gnomad MID

AF:

0.149

Gnomad NFE

AF:

0.144

Gnomad OTH

AF:

0.124

GnomAD4 exome

AF:

0.0667

AC:

AN:

Hom.:

AF XY:

0.00

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.0500

AC:

AN:

Other (OTH)

AF:

0.167

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

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:

0.116

AC:

17722

AN:

152160

Hom.:

1396

Cov.:

AF XY:

0.119

AC XY:

8887

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0270

AC:

1121

AN:

41528

American (AMR)

AF:

0.0917

AC:

1402

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.153

AC:

530

AN:

3468

East Asian (EAS)

AF:

0.311

AC:

1606

AN:

5164

South Asian (SAS)

AF:

0.257

AC:

1239

AN:

4818

European-Finnish (FIN)

AF:

0.157

AC:

1666

AN:

10578

Middle Eastern (MID)

AF:

0.156

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.144

AC:

9805

AN:

67992

Other (OTH)

AF:

0.125

AC:

264

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

767

1534

2301

3068

3835

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

214

428

642

856

1070

<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:

0.128

Hom.:

765

Bravo

AF:

0.107

Asia WGS

AF:

0.249

AC:

868

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.94

(source)

DANN

Benign

0.70

PhyloP100

-0.19

PromoterAI

-0.015

Neutral

(source)

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