Genetic Variant EIF4H:c.469+963C>T (chr7-74191269-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_022170.2(EIF4H):c.469+963C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00838 in 533,556 control chromosomes in the GnomAD database, including 145 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 0.022 ( 112 hom., cov: 32)

Exomes 𝑓: 0.0030 ( 33 hom. )

Consequence

EIF4H
NM_022170.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.400

Publications

12 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:

MIR590 (HGNC:32846): (microRNA 590) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

MIR590 links:

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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=-0.58).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EIF4H	NM_022170.2	MANE Select	c.469+963C>T	intron	N/A	NP_071496.1	Q15056-1
EIF4H	NM_031992.2		c.409+1351C>T	intron	N/A	NP_114381.1	Q15056-2
MIR590	NR_030321.1		n.72C>T	non_coding_transcript_exon	Exon 1 of 1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
EIF4H	ENST00000265753.13	TSL:2 MANE Select	c.469+963C>T	intron	N/A	ENSP00000265753.8	Q15056-1
EIF4H	ENST00000353999.6	TSL:1	c.409+1351C>T	intron	N/A	ENSP00000265754.8	Q15056-2
EIF4H	ENST00000678341.1		c.460+963C>T	intron	N/A	ENSP00000504041.1	A0A7I2V4E4

Frequencies

GnomAD3 genomes

AF:

0.0217

AC:

3309

AN:

152182

Hom.:

107

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0734

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000323

Gnomad OTH

AF:

0.0215

GnomAD2 exomes

AF:

0.00568

AC:

1423

AN:

250318

AF XY:

0.00427

show subpopulations

Gnomad AFR exome

AF:

0.0730

Gnomad AMR exome

AF:

0.00503

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000362

Gnomad OTH exome

AF:

0.00458

GnomAD4 exome

AF:

0.00299

AC:

1140

AN:

381256

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

506

AN XY:

217126

show subpopulations

African (AFR)

AF:

0.0739

AC:

767

AN:

10384

American (AMR)

AF:

0.00516

AC:

187

AN:

36214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11732

East Asian (EAS)

AF:

0.00

AC:

AN:

13100

South Asian (SAS)

AF:

0.000255

AC:

AN:

66634

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32312

Middle Eastern (MID)

AF:

0.00774

AC:

AN:

2454

European-Non Finnish (NFE)

AF:

0.000266

AC:

AN:

191778

Other (OTH)

AF:

0.00595

AC:

AN:

16648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.0219

AC:

3330

AN:

152300

Hom.:

112

Cov.:

AF XY:

0.0211

AC XY:

1573

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0737

AC:

3061

AN:

41544

American (AMR)

AF:

0.0128

AC:

196

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000323

AC:

AN:

68034

Other (OTH)

AF:

0.0213

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.00990

Hom.:

Bravo

AF:

0.0246

Asia WGS

AF:

0.00635

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

8.0

(source)

DANN

Benign

0.63

PhyloP100

0.40

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