Genetic Variant NM_021170.4:c.629A>T (chr1-999096-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_021170.4(HES4):c.629A>T(p.Gln210Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HES4
NM_021170.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.769

Publications

0 publications found

Variant links:

Genes affected

HES4 (HGNC:24149): (hes family bHLH transcription factor 4) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in anterior/posterior pattern specification and regulation of transcription by RNA polymerase II. Predicted to be part of chromatin. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HES4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13052747).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021170.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HES4	NM_021170.4	MANE Select	c.629A>T	p.Gln210Leu	missense	Exon 4 of 4	NP_066993.1	Q9HCC6
HES4	NM_001142467.2		c.707A>T	p.Gln236Leu	missense	Exon 3 of 3	NP_001135939.1	E9PB28
HES4	NM_001410700.1		c.533A>T	p.Gln178Leu	missense	Exon 3 of 3	NP_001397629.1	D6REB3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HES4	ENST00000304952.11	TSL:1 MANE Select	c.629A>T	p.Gln210Leu	missense	Exon 4 of 4	ENSP00000304595.7	Q9HCC6
HES4	ENST00000428771.6	TSL:2	c.707A>T	p.Gln236Leu	missense	Exon 3 of 3	ENSP00000393198.2	E9PB28
HES4	ENST00000854802.1		c.569A>T	p.Gln190Leu	missense	Exon 4 of 4	ENSP00000524863.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1071012

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

507706

African (AFR)

AF:

0.00

AC:

AN:

22398

American (AMR)

AF:

0.00

AC:

AN:

8512

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13196

East Asian (EAS)

AF:

0.00

AC:

AN:

24996

South Asian (SAS)

AF:

0.00

AC:

AN:

20498

European-Finnish (FIN)

AF:

0.00

AC:

AN:

21260

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3586

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

914116

Other (OTH)

AF:

0.00

AC:

AN:

42450

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Benign

0.65

DEOGEN2

Benign

0.0015

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.040

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.31

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

PhyloP100

-0.77

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.19

REVEL

Benign

0.055

Sift

Benign

0.36

Sift4G

Benign

0.30

Polyphen

0.0010

Vest4

0.097

MutPred

0.39

Loss of solvent accessibility (P = 0.0015)

MVP

0.36

MPC

0.57

ClinPred

0.21

GERP RS

-5.5

Varity_R

0.056

gMVP

0.54

Mutation Taster

=97/3

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over