rs721917

Positions:

• chr10-79946568-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003019.5(SFTPD):​c.92T>C​(p.Met31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.439 in 1,613,692 control chromosomes in the GnomAD database, including 159,571 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.43 (14337 hom., cov: 33)
  • Exomes 𝑓: 0.44 (145234 hom.)
• Consequence: SFTPD NM_003019.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.186

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.5746423E-6).
• BP6: Variant 10-79946568-A-G is Benign according to our data. Variant chr10-79946568-A-G is described in ClinVar as [Benign]. Clinvar id is 165219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.669 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SFTPD	NM_003019.5	c.92T>C	p.Met31Thr	missense_variant	2/8	ENST00000372292.8	NP_003010.4
SFTPD	XM_011540087.2	c.92T>C	p.Met31Thr	missense_variant	2/8		XP_011538389.1
SFTPD	XM_011540088.3	c.92T>C	p.Met31Thr	missense_variant	2/7		XP_011538390.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SFTPD	ENST00000372292.8	c.92T>C	p.Met31Thr	missense_variant	2/8	1	NM_003019.5	ENSP00000361366.3
SFTPD	ENST00000444384.3	c.131T>C	p.Met44Thr	missense_variant	2/6	3		ENSP00000394325.1
ENSG00000283913	ENST00000421889.1	n.334-3460A>G		intron_variant		3
ENSG00000283913	ENST00000453174.7	n.962-3460A>G		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65259 AN: 152002 Hom.: 14309 Cov.: 33

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.414

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.611

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.407

GnomAD3 exomes AF: 0.466 AC: 117072 AN: 251222 Hom.: 28639 AF XY: 0.476 AC XY: 64660 AN XY: 135778

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.442

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.630

Gnomad SAS exome AF: 0.673

Gnomad FIN exome AF: 0.388

Gnomad NFE exome AF: 0.421

Gnomad OTH exome AF: 0.440

GnomAD4 exome AF: 0.440 AC: 643401 AN: 1461572 Hom.: 145234 Cov.: 41 AF XY: 0.447 AC XY: 325140 AN XY: 727086

Gnomad4 AFR exome AF: 0.400

Gnomad4 AMR exome AF: 0.440

Gnomad4 ASJ exome AF: 0.404

Gnomad4 EAS exome AF: 0.603

Gnomad4 SAS exome AF: 0.674

Gnomad4 FIN exome AF: 0.393

Gnomad4 NFE exome AF: 0.421

Gnomad4 OTH exome AF: 0.440

GnomAD4 genome AF: 0.430 AC: 65341 AN: 152120 Hom.: 14337 Cov.: 33 AF XY: 0.433 AC XY: 32206 AN XY: 74346

Gnomad4 AFR AF: 0.405

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.611

Gnomad4 SAS AF: 0.688

Gnomad4 FIN AF: 0.389

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.413

Alfa AF: 0.423 Hom.: 35660

Bravo AF: 0.425

TwinsUK AF: 0.412 AC: 1526

ALSPAC AF: 0.431 AC: 1660

ESP6500AA AF: 0.401 AC: 1769

ESP6500EA AF: 0.420 AC: 3610

ExAC AF: 0.469 AC: 56954

Asia WGS AF: 0.632 AC: 2196 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	This variant is associated with the following publications: (PMID: 21310059, 22509983, 21934714, 22289856, 24111992, 15661913, 23577114, 12032263, 30013576) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 06, 2015

p.Met31Thr in exon 02 of SFTPD: This variant is not expected to have clinical si gnificance because it has been identified in 67% (11088/16508) of South Asian ch romosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute. org; dbSNP rs721917). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.24
DANN	Benign	0.34
DEOGEN2	Benign	0.075	T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.074	T;T
MetaRNN	Benign	0.0000056	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;.
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.16	N;N
REVEL	Uncertain	0.37
Sift	Benign	0.34	T;T
Sift4G	Benign	0.46	T;.
Polyphen		0.0	B;.
Vest4		0.024
MPC		0.20
ClinPred		0.0080	T
GERP RS		-1.4
Varity_R		0.041
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

Publications

LitVar

Other links and lift over

dbSNP: rs721917; hg19: chr10-81706324; COSMIC: COSV64852800;