Genetic Variant NM_153813.3:c.112A>G (chr16-88486010-A-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153813.3(ZFPM1):c.112A>G(p.Thr38Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,438 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T38P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ZFPM1
NM_153813.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31

Publications

0 publications found

Variant links:

Genes affected

ZFPM1 (HGNC:19762): (zinc finger protein, FOG family member 1) Enables RNA polymerase II-specific DNA-binding transcription factor binding activity and transcription corepressor activity. Involved in platelet formation; regulation of definitive erythrocyte differentiation; and regulation of gene expression. Part of transcription repressor complex. [provided by Alliance of Genome Resources, Apr 2022]

ZFPM1 Gene-Disease associations (from GenCC):

congenital heart disease
Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ZFPM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05154878).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153813.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZFPM1	NM_153813.3	MANE Select	c.112A>G	p.Thr38Ala	missense	Exon 2 of 10	NP_722520.2	Q8IX07

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ZFPM1	ENST00000319555.8	TSL:1 MANE Select	c.112A>G	p.Thr38Ala	missense	Exon 2 of 10	ENSP00000326630.2	Q8IX07
ZFPM1	ENST00000569086.5	TSL:2	c.112A>G	p.Thr38Ala	missense	Exon 2 of 6	ENSP00000482796.1	A0A087WZP1
ZFPM1	ENST00000562437.2	TSL:2	c.112A>G	p.Thr38Ala	missense	Exon 2 of 5	ENSP00000480412.1	A0A087WWQ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.85e-7

AC:

AN:

1460438

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726490

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44706

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52212

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111866

Other (OTH)

AF:

0.00

AC:

AN:

60362

⚠️ 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: 0.375

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.050

(source)

DANN

Benign

0.20

DEOGEN2

Benign

0.13

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0017

LIST_S2

Benign

0.26

M_CAP

Benign

0.012

MetaRNN

Benign

0.052

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.0

PhyloP100

-1.3

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.47

REVEL

Benign

0.028

Sift

Benign

0.74

Sift4G

Benign

0.77

Polyphen

0.0

Vest4

0.094

MutPred

0.12

Loss of phosphorylation at T38 (P = 0.0089)

MVP

0.067

MPC

0.22

ClinPred

0.038

GERP RS

-7.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.022

gMVP

0.17

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over