chr15-81002693-A-C

Variant names:

• chr15-81002693-A-C
• NM_022566.3:c.422A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_022566.3(TLNRD1):​c.422A>C​(p.Gln141Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q141H) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TLNRD1 NM_022566.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.58
• Publications: 0 publications found

Genes affected

TLNRD1 (HGNC:13519): (talin rod domain containing 1) This gene encodes a protein that is regulated by micro RNA MiR-574-3, and is thought to have an oncogenic function in human bladder cancer. A similar gene in mouse is located in a chromosomal region critical for differentiation of mesoderm, which affects embryo patterning and the formation of heart, muscle, blood, skeleton and the urogenital system. The mouse gene is expressed in early development, and in the adult. [provided by RefSeq, Nov 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLNRD1	NM_022566.3	c.422A>C	p.Gln141Pro	missense_variant	Exon 1 of 1	ENST00000267984.4	NP_072088.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLNRD1	ENST00000267984.4	c.422A>C	p.Gln141Pro	missense_variant	Exon 1 of 1	6	NM_022566.3	ENSP00000267984.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.422A>C (p.Q141P) alteration is located in exon 1 (coding exon 1) of the MESDC1 gene. This alteration results from a A to C substitution at nucleotide position 422, causing the glutamine (Q) at amino acid position 141 to be replaced by a proline (P). 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	Benign	0.18
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.12
Eigen_PC	Benign	0.096
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.0	T
PhyloP100		6.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Benign	0.20	T
Sift4G	Benign	0.095	T
Polyphen		0.95	P
Vest4		0.53
MutPred		0.32		Gain of glycosylation at Q141 (P = 0.0048);
MVP		0.11
MPC		1.9
ClinPred		0.95	D
GERP RS		3.9
Varity_R		0.82
gMVP		0.70

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

Other links and lift over

hg19: chr15-81295034;