chr19-3543669-G-T

Variant names:

• chr19-3543669-G-T
• rs1339123871
• NM_001135580.2:c.437G>T

Variant summary

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

The NM_001135580.2(TEKTIP1):​c.437G>T​(p.Gly146Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,387,314 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TEKTIP1 NM_001135580.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.484

Genes affected

TEKTIP1 (HGNC:34496): (tektin bundle interacting protein 1)

MFSD12 (HGNC:28299): (major facilitator superfamily domain containing 12) Enables cysteine transmembrane transporter activity. Involved in cysteine transmembrane transport; pigment metabolic process involved in pigmentation; and regulation of melanin biosynthetic process. Located in lysosome and melanosome. Part of late endosome. [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 rank	MANE	Protein	UniProt
TEKTIP1	NM_001135580.2	c.437G>T	p.Gly146Val	missense_variant	Exon 3 of 4	ENST00000329493.6	NP_001129052.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TEKTIP1	ENST00000329493.6	c.437G>T	p.Gly146Val	missense_variant	Exon 3 of 4	2	NM_001135580.2	ENSP00000327950.4
TEKTIP1	ENST00000681976.1	c.278G>T	p.Gly93Val	missense_variant	Exon 3 of 4			ENSP00000507755.1
MFSD12	ENST00000398558.8	c.329-692C>A		intron_variant	Intron 3 of 4	2		ENSP00000381566.4
MFSD12	ENST00000615073.4	c.490+1140C>A		intron_variant	Intron 4 of 4	3		ENSP00000478456.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1387314 Hom.: 0 Cov.: 35 AF XY: 0.00000146 AC XY: 1 AN XY: 683764

Gnomad4 AFR exome AF: 0.0000318

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: 0.00

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 21, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.437G>T (p.G146V) alteration is located in exon 3 (coding exon 3) of the C19orf71 gene. This alteration results from a G to T substitution at nucleotide position 437, causing the glycine (G) at amino acid position 146 to be replaced by a valine (V). 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	Benign	-0.010	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.083
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.49	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.9	L
PROVEAN	Pathogenic	-5.9	D
REVEL	Benign	0.25
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.41
MutPred		0.44		Gain of sheet (P = 0.0061);
MVP		0.47
ClinPred		0.95	D
GERP RS		3.4
Varity_R		0.63
gMVP		0.17

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

Publications

LitVar

Other links and lift over

dbSNP: rs1339123871; hg19: chr19-3543667;