7-100826965-G-C

Position:

• chr7-100826965-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363494.1(SLC12A9):​c.-64G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,189,970 control chromosomes in the GnomAD database, including 72,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (8075 hom., cov: 21)
  • Exomes 𝑓: 0.40 (64124 hom.)
• Consequence: SLC12A9 NM_001363494.1 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.17

Genes affected

EPHB4 (HGNC:3395): (EPH receptor B4) Ephrin receptors and their ligands, the ephrins, mediate numerous developmental processes, particularly in the nervous system. Based on their structures and sequence relationships, ephrins are divided into the ephrin-A (EFNA) class, which are anchored to the membrane by a glycosylphosphatidylinositol linkage, and the ephrin-B (EFNB) class, which are transmembrane proteins. The Eph family of receptors are divided into 2 groups based on the similarity of their extracellular domain sequences and their affinities for binding ephrin-A and ephrin-B ligands. Ephrin receptors make up the largest subgroup of the receptor tyrosine kinase (RTK) family. The protein encoded by this gene binds to ephrin-B2 and plays an essential role in vascular development. [provided by RefSeq, Jul 2008]

EPHB4 (HGNC:):

SLC12A9 (HGNC:17435): (solute carrier family 12 member 9) Predicted to enable potassium:chloride symporter activity. Predicted to be involved in cell volume homeostasis; inorganic ion homeostasis; and inorganic ion transmembrane transport. Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 7-100826965-G-C is Benign according to our data. Variant chr7-100826965-G-C is described in ClinVar as [Benign]. Clinvar id is 811002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-100826965-G-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.576 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPHB4	NM_004444.5	c.52+14C>G		intron_variant		ENST00000358173.8	NP_004435.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPHB4	ENST00000358173.8	c.52+14C>G		intron_variant		1	NM_004444.5	ENSP00000350896.3

Frequencies

GnomAD3 genomes AF: 0.457 AC: 47237 AN: 103388 Hom.: 8070 Cov.: 21

Gnomad AFR AF: 0.385

Gnomad AMI AF: 0.519

Gnomad AMR AF: 0.566

Gnomad ASJ AF: 0.421

Gnomad EAS AF: 0.595

Gnomad SAS AF: 0.495

Gnomad FIN AF: 0.437

Gnomad MID AF: 0.588

Gnomad NFE AF: 0.455

Gnomad OTH AF: 0.486

GnomAD3 exomes AF: 0.340 AC: 53470 AN: 157212 Hom.: 8631 AF XY: 0.334 AC XY: 28225 AN XY: 84398

Gnomad AFR exome AF: 0.229

Gnomad AMR exome AF: 0.486

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.558

Gnomad SAS exome AF: 0.350

Gnomad FIN exome AF: 0.263

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.329

GnomAD4 exome AF: 0.398 AC: 431986 AN: 1086486 Hom.: 64124 Cov.: 33 AF XY: 0.400 AC XY: 213395 AN XY: 533258

Gnomad4 AFR exome AF: 0.343

Gnomad4 AMR exome AF: 0.580

Gnomad4 ASJ exome AF: 0.364

Gnomad4 EAS exome AF: 0.633

Gnomad4 SAS exome AF: 0.466

Gnomad4 FIN exome AF: 0.418

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.415

GnomAD4 genome AF: 0.457 AC: 47264 AN: 103484 Hom.: 8075 Cov.: 21 AF XY: 0.463 AC XY: 23421 AN XY: 50584

Gnomad4 AFR AF: 0.385

Gnomad4 AMR AF: 0.566

Gnomad4 ASJ AF: 0.421

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.437

Gnomad4 NFE AF: 0.455

Gnomad4 OTH AF: 0.487

Alfa AF: 0.152 Hom.: 119

Bravo AF: 0.338

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 11, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Lymphatic malformation 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Capillary malformation-arteriovenous malformation 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	8.4
DANN	Benign	0.46

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: rs2304374; hg19: chr7-100424587; COSMIC: COSV62269907; COSMIC: COSV62269907;