17-74748872-C-A

Position:

• chr17-74748872-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004252.5(NHERF1):​c.26C>A​(p.Ala9Glu) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NHERF1 NM_004252.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.107

Genes affected

NHERF1 (HGNC:11075): (NHERF family PDZ scaffold protein 1) This gene encodes a sodium/hydrogen exchanger regulatory cofactor. The protein interacts with and regulates various proteins including the cystic fibrosis transmembrane conductance regulator and G-protein coupled receptors such as the beta2-adrenergic receptor and the parathyroid hormone 1 receptor. The protein also interacts with proteins that function as linkers between integral membrane and cytoskeletal proteins. The protein localizes to actin-rich structures including membrane ruffles, microvilli, and filopodia. Mutations in this gene result in hypophosphatemic nephrolithiasis/osteoporosis type 2, and loss of heterozygosity of this gene is implicated in breast cancer.[provided by RefSeq, Sep 2009]

SLC9A3R1-AS1 (HGNC:55322): (SLC9A3R1 antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06147182).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NHERF1	NM_004252.5	c.26C>A	p.Ala9Glu	missense_variant	1/6	ENST00000262613.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NHERF1	ENST00000262613.10	c.26C>A	p.Ala9Glu	missense_variant	1/6	1	NM_004252.5	P1
SLC9A3R1-AS1	ENST00000585285.1	n.41G>T		non_coding_transcript_exon_variant	1/2	3
NHERF1	ENST00000583369.5	c.26C>A	p.Ala9Glu	missense_variant	1/3	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1443138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717640

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

NHERF1-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 10, 2023

The NHERF1 c.26C>A variant is predicted to result in the amino acid substitution p.Ala9Glu. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Benign	0.0020	T;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.31	T;T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.061	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.23	.;N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	0.68	.;N
REVEL	Benign	0.029
Sift	Benign	0.40	.;T
Sift4G	Benign	0.55	T;T
Polyphen		0.0020	.;B
Vest4		0.097
MutPred		0.39		Gain of solvent accessibility (P = 0.0261);Gain of solvent accessibility (P = 0.0261);
MVP		0.29
MPC		1.0
ClinPred		0.11	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.052
gMVP		0.30

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-72745011;