chr11-119187391-C-A

Variant names:

• chr11-119187391-C-A
• rs1949036774
• NM_001168468.2:c.452C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001168468.2(NHERF4):​c.452C>A​(p.Pro151Gln) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P151L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NHERF4 NM_001168468.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.695
• Publications: 0 publications found

Genes affected

NHERF4 (HGNC:19891): (NHERF family PDZ scaffold protein 4) Guanylyl cyclase C (GCC, or GUCY2C; MIM 601330) produces cGMP following the binding of either endogenous ligands or heat-stable enterotoxins secreted by E. coli and other enteric bacteria. Activation of GCC initiates a signaling cascade that leads to phosphorylation of the cystic fibrosis transmembrane conductance regulator (CFTR; MIM 602421), followed by a net efflux of ions and water into the intestinal lumen. IKEPP is a regulatory protein that associates with GCC and regulates the amount of cGMP produced following receptor stimulation (Scott et al., 2002 [PubMed 11950846]).[supplied by OMIM, Mar 2008]

ACMG classification

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=0.09779009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NHERF4	NM_001168468.2	c.452C>A	p.Pro151Gln	missense_variant	Exon 5 of 11	ENST00000355547.10	NP_001161940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NHERF4	ENST00000355547.10	c.452C>A	p.Pro151Gln	missense_variant	Exon 5 of 11	1	NM_001168468.2	ENSP00000347742.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	11
DANN	Benign	0.94
DEOGEN2	Benign	0.032	.;T;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.16	N
LIST_S2	Benign	0.49	T;T;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	.;L;.;.
PhyloP100		0.69
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.93	N;N;N;N
REVEL	Benign	0.039
Sift	Benign	0.20	T;T;T;T
Sift4G	Benign	0.48	T;T;T;T
Polyphen		0.067	B;B;B;.
Vest4		0.15
MutPred		0.41		.;Gain of solvent accessibility (P = 0.0202);.;.;
MVP		0.57
MPC		0.14
ClinPred		0.12	T
GERP RS		3.5
Varity_R		0.049
gMVP		0.22
Mutation Taster		=89/11	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: rs1949036774; hg19: chr11-119058100;