11-78064306-C-T

Position:

• chr11-78064306-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003251.4(THRSP):​c.425C>T​(p.Thr142Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0122 in 1,610,652 control chromosomes in the GnomAD database, including 178 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0086 (7 hom., cov: 32)
  • Exomes 𝑓: 0.013 (171 hom.)
• Consequence: THRSP NM_003251.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.68

Genes affected

THRSP (HGNC:11800): (thyroid hormone responsive) The protein encoded by this gene is similar to the gene product of S14, a rat gene whose expression is limited to liver and adipose tissue and is controlled by nutritional and hormonal factors. This gene has been shown to be expressed in liver and adipocytes, particularly in lipomatous modules. It is also found to be expressed in lipogenic breast cancers, which suggests a role in controlling tumor lipid metabolism. [provided by RefSeq, Jul 2008]

NDUFC2-KCTD14 (HGNC:42956): (NDUFC2-KCTD14 readthrough) This locus represents naturally occurring read-through transcription between the neighboring NDUFC2 (NADH dehydrogenase (ubiquinone) 1, subcomplex unknown, 2, 14.5kDa) and KCTD14 (potassium channel tetramerisation domain containing 14) genes on chromosome 11. The read-through transcripts share sequence identity with the upstream gene product and one variant has a frameshifted C-terminal region derived from the downstream gene exons. [provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039934516).
• BP6: Variant 11-78064306-C-T is Benign according to our data. Variant chr11-78064306-C-T is described in ClinVar as [Benign]. Clinvar id is 771892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THRSP	NM_003251.4	c.425C>T	p.Thr142Met	missense_variant	1/2	ENST00000281030.2	NP_003242.1
NDUFC2-KCTD14	NM_001203260.2	c.310+8692G>A		intron_variant			NP_001190189.1
NDUFC2-KCTD14	NM_001203261.2	c.310+8692G>A		intron_variant			NP_001190190.1
NDUFC2-KCTD14	NM_001203262.2	c.166+15273G>A		intron_variant			NP_001190191.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THRSP	ENST00000281030.2	c.425C>T	p.Thr142Met	missense_variant	1/2	1	NM_003251.4	ENSP00000281030.2
NDUFC2-KCTD14	ENST00000612612.5	c.310+8692G>A		intron_variant		2		ENSP00000478766.1

Frequencies

GnomAD3 genomes AF: 0.00858 AC: 1301 AN: 151720 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00271

Gnomad AMI AF: 0.00549

Gnomad AMR AF: 0.00506

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00292

Gnomad FIN AF: 0.00720

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0148

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00807 AC: 2004 AN: 248190 Hom.: 20 AF XY: 0.00814 AC XY: 1092 AN XY: 134228

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00325

Gnomad ASJ exome AF: 0.000723

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.00387

Gnomad FIN exome AF: 0.00812

Gnomad NFE exome AF: 0.0134

Gnomad OTH exome AF: 0.0108

GnomAD4 exome AF: 0.0126 AC: 18331 AN: 1458816 Hom.: 171 Cov.: 31 AF XY: 0.0121 AC XY: 8803 AN XY: 725604

Gnomad4 AFR exome AF: 0.00180

Gnomad4 AMR exome AF: 0.00400

Gnomad4 ASJ exome AF: 0.00112

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.00387

Gnomad4 FIN exome AF: 0.00858

Gnomad4 NFE exome AF: 0.0149

Gnomad4 OTH exome AF: 0.0112

GnomAD4 genome AF: 0.00857 AC: 1301 AN: 151836 Hom.: 7 Cov.: 32 AF XY: 0.00819 AC XY: 607 AN XY: 74150

Gnomad4 AFR AF: 0.00270

Gnomad4 AMR AF: 0.00505

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.000390

Gnomad4 SAS AF: 0.00292

Gnomad4 FIN AF: 0.00720

Gnomad4 NFE AF: 0.0148

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.0124 Hom.: 21

Bravo AF: 0.00807

TwinsUK AF: 0.0200 AC: 74

ALSPAC AF: 0.0150 AC: 58

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0146 AC: 125

ExAC AF: 0.00781 AC: 948

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.052	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.0066	N
LIST_S2	Benign	0.57	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.037
Sift	Benign	0.19	T
Sift4G	Benign	0.20	T
Polyphen		0.32	B
Vest4		0.097
MVP		0.067
MPC		0.16
ClinPred		0.013	T
GERP RS		0.77
Varity_R		0.018
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs117003832; hg19: chr11-77775352; COSMIC: COSV55246217; COSMIC: COSV55246217;