7-74194806-C-G

Variant names:

• chr7-74194806-C-G
• rs202047154
• NM_022170.2:c.535C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_022170.2(EIF4H):​c.535C>G​(p.Pro179Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,605,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P179S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: EIF4H NM_022170.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90
• Publications: 1 publications found

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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0634242).
• BS2: High AC in GnomAd4 at 18 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.535C>G	p.Pro179Ala	missense	Exon 6 of 7	NP_071496.1	Q15056-1
	EIF4H	NM_031992.2		c.475C>G	p.Pro159Ala	missense	Exon 5 of 6	NP_114381.1	Q15056-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EIF4H	ENST00000265753.13	TSL:2 MANE Select	c.535C>G	p.Pro179Ala	missense	Exon 6 of 7	ENSP00000265753.8	Q15056-1
	EIF4H	ENST00000353999.6	TSL:1	c.475C>G	p.Pro159Ala	missense	Exon 5 of 6	ENSP00000265754.8	Q15056-2
	EIF4H	ENST00000678341.1		c.526C>G	p.Pro176Ala	missense	Exon 6 of 7	ENSP00000504041.1	A0A7I2V4E4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000926 AC: 23 AN: 248374 AF XY: 0.0000966

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000180

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000232 AC: 337 AN: 1453480 Hom.: 0 Cov.: 31 AF XY: 0.000244 AC XY: 176 AN XY: 721054

African (AFR) AF: 0.0000300 AC: 1 AN: 33334

American (AMR) AF: 0.00 AC: 0 AN: 44570

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26072

East Asian (EAS) AF: 0.0000508 AC: 2 AN: 39360

South Asian (SAS) AF: 0.0000349 AC: 3 AN: 86018

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.000348 AC: 2 AN: 5752

European-Non Finnish (NFE) AF: 0.000295 AC: 326 AN: 1105056

Other (OTH) AF: 0.0000500 AC: 3 AN: 59970

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74498

African (AFR) AF: 0.000120 AC: 5 AN: 41594

American (AMR) AF: 0.00 AC: 0 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000176 AC: 12 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000982

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000109

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.047
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	18
DANN	Benign	0.84
DEOGEN2	Benign	0.093	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.0037	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.9
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.058
Sift	Benign	0.68	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.26
MVP		0.27
MPC		0.14
ClinPred		0.013	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.35
Mutation Taster		=87/13	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

Other links and lift over

dbSNP: rs202047154; hg19: chr7-73609136; COSMIC: COSV56082161; COSMIC: COSV56082161;