Genetic Variant EIF4H:p.Asp9Asn (chr7-74174408-G-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_022170.2(EIF4H):c.25G>A(p.Asp9Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000993 in 1,460,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

EIF4H
NM_022170.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.06

Publications

1 publications found

Variant links:

Genes affected

EIF4H (HGNC:12741): (eukaryotic translation initiation factor 4H) This gene encodes one of the translation initiation factors, which functions to stimulate the initiation of protein synthesis at the level of mRNA utilization. This gene is deleted in Williams syndrome, a multisystem developmental disorder caused by the deletion of contiguous genes at 7q11.23. Alternative splicing of this gene generates 2 transcript variants. [provided by RefSeq, Jul 2008]

EIF4H links:

ENSG00000301571 (HGNC:):

ENSG00000301571 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.14362231).

BS2

High AC in GnomAd4 at 70 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022170.2. 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
	EIF4H	NM_022170.2	MANE Select	c.25G>A	p.Asp9Asn	missense	Exon 1 of 7	NP_071496.1	Q15056-1
	EIF4H	NM_031992.2		c.25G>A	p.Asp9Asn	missense	Exon 1 of 6	NP_114381.1	Q15056-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EIF4H	ENST00000265753.13	TSL:2 MANE Select	c.25G>A	p.Asp9Asn	missense	Exon 1 of 7	ENSP00000265753.8	Q15056-1
EIF4H	ENST00000353999.6	TSL:1	c.25G>A	p.Asp9Asn	missense	Exon 1 of 6	ENSP00000265754.8	Q15056-2
EIF4H	ENST00000679266.1		c.-468G>A		5_prime_UTR	Exon 1 of 8	ENSP00000503412.1	A0A7I2V3E4

Frequencies

GnomAD3 genomes

AF:

0.000464

AC:

AN:

150892

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00119

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

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:

0.000104

AC:

AN:

191946

AF XY:

0.0000843

show subpopulations

Gnomad AFR exome

AF:

0.00116

Gnomad AMR exome

AF:

0.000243

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000573

AC:

AN:

1309394

Hom.:

Cov.:

AF XY:

0.0000584

AC XY:

AN XY:

650586

show subpopulations

African (AFR)

AF:

0.00142

AC:

AN:

27396

American (AMR)

AF:

0.000448

AC:

AN:

33504

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21374

East Asian (EAS)

AF:

0.00

AC:

AN:

29356

South Asian (SAS)

AF:

0.0000292

AC:

AN:

68424

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48178

Middle Eastern (MID)

AF:

0.000206

AC:

AN:

4852

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1024850

Other (OTH)

AF:

0.000117

AC:

AN:

51460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

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:

0.000464

AC:

AN:

151000

Hom.:

Cov.:

AF XY:

0.000379

AC XY:

AN XY:

73792

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41366

American (AMR)

AF:

0.00138

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3458

East Asian (EAS)

AF:

0.00

AC:

AN:

5136

South Asian (SAS)

AF:

0.00

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10192

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67554

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000162

Hom.:

Bravo

AF:

0.000665

ESP6500AA

AF:

0.00114

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000108

AC:

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

Uncertain

0.55

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Benign

0.12

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.67

MetaRNN

Benign

0.14

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

7.1

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.79

REVEL

Benign

0.10

Sift

Pathogenic

0.0

Sift4G

Benign

0.28

Polyphen

0.94

Vest4

0.49

MVP

0.57

MPC

2.2

ClinPred

0.099

GERP RS

3.2

PromoterAI

-0.018

Neutral

(source)

Varity_R

0.56

gMVP

0.53

Mutation Taster

=70/30

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over