4-146258757-C-T

Position:

• chr4-146258757-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001029998.6(SLC10A7):​c.928G>A​(p.Ala310Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00484 in 1,611,368 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0049 (26 hom.)
• Consequence: SLC10A7 NM_001029998.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.57

Genes affected

SLC10A7 (HGNC:23088): (solute carrier family 10 member 7) Enables bile acid transmembrane transporter activity. Involved in several processes, including cellular calcium ion homeostasis; glycoprotein transport; and heparin biosynthetic process. Located in Golgi apparatus and endoplasmic reticulum. Is intrinsic component of plasma membrane. [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 (MetaRNN=0.011707991).
• BP6: Variant 4-146258757-C-T is Benign according to our data. Variant chr4-146258757-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 713617.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0038 (579/152258) while in subpopulation NFE AF= 0.00567 (386/68024). AF 95% confidence interval is 0.00521. There are 3 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SLC10A7	NM_001029998.6	c.928G>A	p.Ala310Thr	missense_variant	11/12	ENST00000335472.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SLC10A7	ENST00000335472.12	c.928G>A	p.Ala310Thr	missense_variant	11/12	1	NM_001029998.6	P1
SLC10A7	ENST00000507030.5	c.928G>A	p.Ala310Thr	missense_variant	11/13	1
SLC10A7	ENST00000432059.6	c.889G>A	p.Ala297Thr	missense_variant	10/11	1
SLC10A7	ENST00000693222.1	c.1018G>A	p.Ala340Thr	missense_variant	12/13

Frequencies

GnomAD3 genomes AF: 0.00381 AC: 579 AN: 152140 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00877

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00567

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00473 AC: 1174 AN: 248422 Hom.: 7 AF XY: 0.00465 AC XY: 625 AN XY: 134372

Gnomad AFR exome AF: 0.000744

Gnomad AMR exome AF: 0.000358

Gnomad ASJ exome AF: 0.00639

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000335

Gnomad FIN exome AF: 0.00963

Gnomad NFE exome AF: 0.00751

Gnomad OTH exome AF: 0.00462

GnomAD4 exome AF: 0.00495 AC: 7220 AN: 1459110 Hom.: 26 Cov.: 31 AF XY: 0.00483 AC XY: 3506 AN XY: 725902

Gnomad4 AFR exome AF: 0.000751

Gnomad4 AMR exome AF: 0.000343

Gnomad4 ASJ exome AF: 0.00698

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000701

Gnomad4 FIN exome AF: 0.00967

Gnomad4 NFE exome AF: 0.00558

Gnomad4 OTH exome AF: 0.00454

GnomAD4 genome AF: 0.00380 AC: 579 AN: 152258 Hom.: 3 Cov.: 32 AF XY: 0.00395 AC XY: 294 AN XY: 74454

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00877

Gnomad4 NFE AF: 0.00567

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00531 Hom.: 5

Bravo AF: 0.00342

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00545 AC: 21

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00558 AC: 48

ExAC AF: 0.00600 AC: 729

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00518

EpiControl AF: 0.00439

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	SLC10A7: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -

SLC10A7-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	21
DANN	Benign	0.26
DEOGEN2	Benign	0.0045	.;T;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.029
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	.;N;N
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.34	T
PROVEAN	Benign	2.0	N;N;N
REVEL	Benign	0.085
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.30
MVP		0.055
MPC		0.39
ClinPred		0.021	T
GERP RS		5.6
Varity_R		0.16
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs138035413; hg19: chr4-147179909; COSMIC: COSV99390227;