NM_003019.5:c.743A>G

Variant names:

• chr10-79940713-T-C
• rs1842602162
• NM_003019.5:c.743A>G

Variant summary

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

The NM_003019.5(SFTPD):​c.743A>G​(p.Tyr248Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,970 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SFTPD NM_003019.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.30

Genes affected

SFTPD (HGNC:10803): (surfactant protein D) The protein encoded by this gene is part of the innate immune response, protecting the lungs against inhaled microorganisms and chemicals. The encoded protein may also be involved in surfactant metabolism. [provided by RefSeq, Jul 2015]

ENSG00000283913 (HGNC:):

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
SFTPD	NM_003019.5	c.743A>G	p.Tyr248Cys	missense_variant	Exon 7 of 8	ENST00000372292.8	NP_003010.4
SFTPD	XM_011540087.2	c.743A>G	p.Tyr248Cys	missense_variant	Exon 7 of 8		XP_011538389.1
SFTPD	XM_011540088.3	c.626A>G	p.Tyr209Cys	missense_variant	Exon 6 of 7		XP_011538390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SFTPD	ENST00000372292.8	c.743A>G	p.Tyr248Cys	missense_variant	Exon 7 of 8	1	NM_003019.5	ENSP00000361366.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450970 Hom.: 0 Cov.: 28 AF XY: 0.00000277 AC XY: 2 AN XY: 721796

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 28, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.743A>G (p.Y248C) alteration is located in exon 7 (coding exon 6) of the SFTPD gene. This alteration results from a A to G substitution at nucleotide position 743, causing the tyrosine (Y) at amino acid position 248 to be replaced by a cysteine (C). 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	0.62
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Uncertain	0.53	D
Eigen	Benign	0.013
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.041	D
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.49
Sift	Benign	0.049	D
Sift4G	Benign	0.080	T
Polyphen		1.0	D
Vest4		0.31
MutPred		0.70		Gain of methylation at K249 (P = 0.0123);
MVP		0.95
MPC		0.27
ClinPred		0.48	T
GERP RS		3.4
Varity_R		0.45
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1842602162; hg19: chr10-81700469;