7-74174408-G-A

Variant names:

• chr7-74174408-G-A
• rs146609826
• NM_022170.2:c.25G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.06

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]

ACMG classification

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EIF4H	NM_022170.2	c.25G>A	p.Asp9Asn	missense_variant	Exon 1 of 7	ENST00000265753.13	NP_071496.1
EIF4H	NM_031992.2	c.25G>A	p.Asp9Asn	missense_variant	Exon 1 of 6		NP_114381.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EIF4H	ENST00000265753.13	c.25G>A	p.Asp9Asn	missense_variant	Exon 1 of 7	2	NM_022170.2	ENSP00000265753.8

Frequencies

GnomAD3 genomes AF: 0.000464 AC: 70 AN: 150892 Hom.: 0 Cov.: 32

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: 20 AN: 191946 AF XY: 0.0000843

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: 75 AN: 1309394 Hom.: 0 Cov.: 30 AF XY: 0.0000584 AC XY: 38 AN XY: 650586

Gnomad4 AFR exome AF: 0.00142 AC: 39 AN: 27396

Gnomad4 AMR exome AF: 0.000448 AC: 15 AN: 33504

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 21374

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 29356

Gnomad4 SAS exome AF: 0.0000292 AC: 2 AN: 68424

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 48178

Gnomad4 NFE exome AF: 0.0000117 AC: 12 AN: 1024850

Gnomad4 Remaining exome AF: 0.000117 AC: 6 AN: 51460

GnomAD4 genome AF: 0.000464 AC: 70 AN: 151000 Hom.: 0 Cov.: 32 AF XY: 0.000379 AC XY: 28 AN XY: 73792

Gnomad4 AFR AF: 0.00118 AC: 0.00118455 AN: 0.00118455

Gnomad4 AMR AF: 0.00138 AC: 0.00138285 AN: 0.00138285

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000162 Hom.: 0

Bravo AF: 0.000665

ESP6500AA AF: 0.00114 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000108 AC: 13

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 01, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.25G>A (p.D9N) alteration is located in exon 1 (coding exon 1) of the EIF4H gene. This alteration results from a G to A substitution at nucleotide position 25, causing the aspartic acid (D) at amino acid position 9 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.11	T;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.67	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.79	N;N
REVEL	Benign	0.10
Sift	Pathogenic	0.0	D;T
Sift4G	Benign	0.28	T;T
Polyphen		0.94	P;D
Vest4		0.49
MVP		0.57
MPC		2.2
ClinPred		0.099	T
GERP RS		3.2
Varity_R		0.56
gMVP		0.53
Mutation Taster		=70/30	polymorphism

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

LitVar

Other links and lift over

dbSNP: rs146609826; hg19: chr7-73588738; COSMIC: COSV99072826;