chr17-28724680-G-C

Variant names:

• chr17-28724680-G-C
• NM_138463.4:c.574C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_138463.4(TLCD1):​c.574C>G​(p.His192Asp) 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. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLCD1 NM_138463.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.911
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17439187).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLCD1	NM_138463.4	c.574C>G	p.His192Asp	missense_variant	Exon 4 of 4	ENST00000292090.8	NP_612472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLCD1	ENST00000292090.8	c.574C>G	p.His192Asp	missense_variant	Exon 4 of 4	1	NM_138463.4	ENSP00000292090.3
TLCD1	ENST00000394933.7	c.433C>G	p.His145Asp	missense_variant	Exon 4 of 4	2		ENSP00000378391.3
TLCD1	ENST00000580518.1	c.361C>G	p.His121Asp	missense_variant	Exon 4 of 4	3		ENSP00000466264.1
TLCD1	ENST00000581236.1	c.111-27C>G		intron_variant	Intron 1 of 1	2		ENSP00000468670.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.574C>G (p.H192D) alteration is located in exon 4 (coding exon 4) of the TLCD1 gene. This alteration results from a C to G substitution at nucleotide position 574, causing the histidine (H) at amino acid position 192 to be replaced by an aspartic acid (D). 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	0.16
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.91
DEOGEN2	Uncertain	0.53	D;.;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	0.0	N;.;.
PhyloP100		0.91
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.2	N;N;.
REVEL	Benign	0.20
Sift	Benign	0.11	T;T;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.092	B;.;.
Vest4		0.39
MutPred		0.52		Gain of relative solvent accessibility (P = 0.1259);.;.;
MVP		0.33
MPC		0.66
ClinPred		0.070	T
GERP RS		-2.5
PromoterAI		0.0020	Neutral
Varity_R		0.071
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: chr17-27051698;