chr17-28725350-C-T

Variant names:

• chr17-28725350-C-T
• rs201160951
• NM_138463.4:c.314G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138463.4(TLCD1):​c.314G>A​(p.Ser105Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S105T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TLCD1 NM_138463.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.56
• Publications: 0 publications found

Genes affected

TLCD1 (HGNC:25177): (TLC domain containing 1) Involved in several processes, including membrane assembly; phospholipid homeostasis; and regulation of membrane lipid distribution. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049678385).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD1	NM_138463.4	c.314G>A	p.Ser105Asn	missense_variant	Exon 3 of 4	ENST00000292090.8	NP_612472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLCD1	ENST00000292090.8	c.314G>A	p.Ser105Asn	missense_variant	Exon 3 of 4	1	NM_138463.4	ENSP00000292090.3
TLCD1	ENST00000394933.7	c.173G>A	p.Ser58Asn	missense_variant	Exon 3 of 4	2		ENSP00000378391.3
TLCD1	ENST00000580518.1	c.101G>A	p.Ser34Asn	missense_variant	Exon 3 of 4	3		ENSP00000466264.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.000422 AC: 104 AN: 246314 AF XY: 0.000306

Gnomad AFR exome AF: 0.000393

Gnomad AMR exome AF: 0.0000872

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00100

Gnomad FIN exome AF: 0.000237

Gnomad NFE exome AF: 0.000621

Gnomad OTH exome AF: 0.000168

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000390 AC: 57 AN: 1459938 Hom.: 0 Cov.: 33 AF XY: 0.0000427 AC XY: 31 AN XY: 726298

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.000925 AC: 48 AN: 51918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1111794

Other (OTH) AF: 0.0000166 AC: 1 AN: 60214

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000991 AC: 12

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Benign	0.79
DEOGEN2	Benign	0.22	T;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	-0.76	N;.;.
PhyloP100		2.6
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	1.5	N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.99	T;T;.
Sift4G	Benign	0.62	T;T;.
Polyphen		0.0030	B;.;.
Vest4		0.18
MVP		0.51
MPC		0.38
ClinPred		0.043	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.41

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

dbSNP: rs201160951; hg19: chr17-27052368;