2-137057210-T-G

Position:

• chr2-137057210-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001316349.2(THSD7B):​c.930T>G​(p.Asp310Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,136 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: THSD7B NM_001316349.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0710

Genes affected

THSD7B (HGNC:29348): (thrombospondin type 1 domain containing 7B) Predicted to be involved in actin cytoskeleton reorganization. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
THSD7B	NM_001316349.2	c.930T>G	p.Asp310Glu	missense_variant	3/28	ENST00000409968.6	NP_001303278.1
THSD7B	XM_047445935.1	c.507T>G	p.Asp169Glu	missense_variant	3/28		XP_047301891.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
THSD7B	ENST00000409968.6	c.930T>G	p.Asp310Glu	missense_variant	3/28	5	NM_001316349.2	ENSP00000387145.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460136 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 726204

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2024

The c.837T>G (p.D279E) alteration is located in exon 2 (coding exon 2) of the THSD7B gene. This alteration results from a T to G substitution at nucleotide position 837, causing the aspartic acid (D) at amino acid position 279 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.023	T;.;T
Eigen	Benign	0.016
Eigen_PC	Benign	-0.070
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.83	T;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T;T;T
MetaSVM	Benign	-0.85	T
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.33
Sift	Uncertain	0.012	D;D;D
Sift4G	Uncertain	0.012	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.58
MutPred		0.37		Gain of disorder (P = 0.1453);Gain of disorder (P = 0.1453);.;
MVP		0.13
MPC		0.59
ClinPred		0.98	D
GERP RS		-1.1
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 20

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1260352260; hg19: chr2-137814780;